JP2023533014A - long-acting formulation - Google Patents

Abstract

The present invention comprises micro- or nanoparticles of the anti-TB compound bedaquiline, suspended in a pharmaceutically acceptable aqueous carrier, and PEG4000 as a surface-modifying agent, for administration by intramuscular or subcutaneous injection. and the use of such pharmaceutical compositions in the treatment and prevention of pathogenic mycobacterial infections.

Description

The present invention is a microscopic preparation of the ATP synthase inhibitor compound, bedaquiline (commercially available as Sirturo®, where bedaquiline is in the form of its fumarate salt), suspended in a pharmaceutically acceptable aqueous carrier. or nanoparticles for administration by intramuscular or subcutaneous injection and the use of such pharmaceutical compositions in the treatment of bacterial infections such as tuberculosis.

Bedaquiline is a known antituberculous drug that is used in various combinations. It can be formulated in the form of a pharmaceutically acceptable salt, such as the form of bedaquiline fumarate, marketed as Sirturo®. It is believed to function as an ATP synthase inhibitor, with a selectivity index for mycobacterial ATP synthase greater than 20,000 versus eukaryotic mitochondrial ATP synthase.

Bedaquiline is useful for the treatment of mycobacterial infections, as well as for killing dormant, latent, persistent mycobacteria, particularly Mycobacterium tuberculosis. As a result, it has already been reported that it can be used to treat latent TB. Such uses of bedaquiline are described in several publications such as WO2004/011436 and WO2006/067048. For example, "Bacterial Activities of R207910 and other Antimicrobial Agents against Mycobacterium leprae in Mice", Antimicrobial agents and Chemotherapy, April 2006, p. 1558, and "The Diarylquinolone R207910 is Bactericidal against Mycobacterium leprae in mice and at Low Dose Administered Intermittently", Antimicrobial It is also known that bedaquiline is bactericidal against Mycobacterium leprae, as described in Agents and Chemotherapy, Sept 2009, p 3989.

The goal of long-acting formulations may be to reduce drug load. This is particularly useful for therapeutic regimes that may last for several months.

The number and/or amount of dosage forms that need to be administered is commonly referred to as the "pill load." A high pill load is undesirable for many reasons, including frequency of ingestion and the need to store and transport multiple or large amounts of pills, often combined with the inconvenience of having to swallow large dosage forms. A high pill load increases the risk that patients will not take their full dose, thereby failing to comply with the prescribed dosing regime. Besides reducing the effectiveness of the treatment, this can lead to the development of resistance (for example, fungal resistance in the case of bedaquiline).

It would be attractive to provide therapy with administration of dosage forms at long intervals, such as one week or longer, or one month or longer.

Various formulations, including long-acting formulations, are known in the art. For example, micro- and nanosuspension technologies have been used in the field of anti-HIV drugs for long-acting formulations, as described, for example, in WO2007/147882 and WO2012/140220. known to achieve Further nanoparticles known in the prior art are described, for example, in EP-A-0499299. Such particles consist of particles of a crystalline drug substance having an average particle size in the submicron range and having surface-modifying agents adsorbed onto their surfaces. Nanoparticles have also been used to formulate poorly water-soluble active ingredients.

Long-acting formulations of the anti-tubercular drug bedaquiline are also described in WO2019/012100.

The importance of long-acting formulations is the intermittent application of these micro- or nanoparticulate formulations at time intervals of one week or longer to produce plasma concentrations that may be sufficient to inhibit the growth of mycobacterial infections. associated with targeted administration. This allows for a reduction in dosing frequency, which is beneficial from a patient pill load and compliance standpoint. Therefore, micro- or nanoparticulate formulations of bedaquiline may be useful in the long-term treatment of mycobacterial infections (eg, tuberculosis, such as latent tuberculosis, and leprosy).

Intermittent administration of micro- or nanoparticulate formulations of bedaquiline at time intervals of one week or more also results in plasma concentrations that may be sufficient to prevent transmission of mycobacterial infections. Again, a reduction in dosing frequency is required, which is again advantageous from a pill burden and compliance standpoint for individuals at risk of being infected.

A problem associated with the manufacture and suitability of such long acting formulations is the fact that they must be sterile (e.g. intended to be administered intravenously, intramuscularly or subcutaneously). (important for injectables, if available). There are many different methods for sterilizing such long acting formulations, such as heat sterilization, autoclaving and gamma irradiation (γ-irradiation). Examples of some methods are described in US Pat. No. 5,298,262, US Pat. No. 5,346,702 and US Patent Application Publication No. 2010/255102. For heat sterilization and autoclaving, it is important to be able to choose excipients (eg, surface modifiers or surfactants) that are autoclavable, eg, do not degrade. desired stability of long-acting formulations, undesirable aggregation of particles of the active pharmaceutical ingredient (API) within the formulation, and desirable resuspendability of the formulation (after sterilization, e.g., autoclaving); A related further problem arises after such sterilization. US Pat. Nos. 5,298,262 and 5,346,702 disclose the use of cloud point modifiers to prevent particle agglomeration during sterilization. The cloud point is the temperature above which a surfactant (or surface modifier) phase separates and precipitates out of solution. Heat sterilization or autoclave sterilization of suspensions can affect surfactants/surface modifiers as they phase separate and precipitate when heated above their cloud temperature due to solubility changes. must be performed below the cloud point of This leaves the particle surface (of the active pharmaceutical ingredient) free and the particles will thereby agglomerate. The idea of cloud point modifiers (or boosters) is to allow the temperature of the sterilization or autoclaving process to be higher, thereby preventing or limiting particle agglomeration. Cloud point modifiers mentioned in US Pat. No. 5,298,262 and US Pat. No. 5,346,702 include sodium dodecyl sulfate, dodecyltrimethylammonium bromide, polyethylene glycol and propylene glycol. ionic and non-ionic cloud point modifiers such as Polyethylene glycols mentioned as cloud point modifiers include PEG 300, PEG 400, PEG 1000 and PEG 2000, with PEG 400 being shown to be preferred, especially PEG 400 and PEG 1000 (of Tetronic 908) having a cloud point of was shown to increase Other cloud point modifiers or boosters are also described in many other publications.

Further alternative and/or improved long-acting formulations are now described and the present invention relates to such formulations.

The present invention
(a) bedaquiline, or a pharmaceutically acceptable salt thereof, in micro- or nanoparticulate form, and a surface modifier;
(b) an intramuscular or subcutaneous injection containing a therapeutically effective amount of bedaquiline, or a pharmaceutically acceptable salt thereof, in the form of a micro- or nanoparticle suspension comprising a pharmaceutically acceptable aqueous carrier; A pharmaceutical composition for administration by
With respect to compositions characterized in that the surface modifier comprises PEG 4000 or the like, such compositions may be referred to herein as "compositions of the invention".

PEG 4000, or polyethylene glycol 4000, is a known high molecular weight polymer where 4000 refers to the approximate average molecular weight in Daltons. PEG 4000 is commercially available from sources such as Sigma-Aldrich, which is why it is used as such. However, in certain embodiments (e.g., where the terms "PEG4000" or "PEG4000, etc." are used), the PEG group, when referred to herein in the context of the present invention, is PEG3000-PEG5000 (e.g., PEG 3500-PEG 4500), but other high molecular weight polyethylene glycols, such as those above 1000 and up to 8000 (eg PEG 1000-PEG 8000, eg PEG 2000-PEG 6000) are included within the scope of the invention. As shown herein, it is understood that most PEGs contain molecules with a distribution of molecular weights, i.e., they are polydisperse systems, the number next to the PEG is Dalton units represents the average molecular weight in

The compositions of the invention are suspensions, thereby meaning that the bedaquiline active ingredient is suspended in a pharmaceutically acceptable aqueous carrier.

The compositions (ie, suspensions) of the present invention contain a surface-modifying agent that can be adsorbed onto the surface of the active ingredient bedaquiline. As indicated, surface modifiers include PEG 4000 and the like (and may also contain other surface modifiers such as those described herein below).

In one embodiment, the present invention therefore provides
(a) bedaquiline, or a pharmaceutically acceptable salt thereof, in micro- or nanoparticulate form having a surface-modifying agent adsorbed to its surface;
(b) by intramuscular or subcutaneous injection of a therapeutically effective amount of bedaquiline or a pharmaceutically acceptable salt thereof in the form of a micro- or nanoparticulate suspension with a pharmaceutically acceptable aqueous carrier; It may relate to a pharmaceutical composition for administration, wherein the bedaquiline active ingredient is suspended and the surface modifier comprises PEG4000 or the like.

The present invention further provides for Mycobacterium tuberculosis, M. tuberculosis. M. bovis, M. M. leprae, M. M. avium and M. avium. The present invention relates to methods of treating subjects infected with pathogenic mycobacteria such as M. marinum. In some embodiments, the mycobacterium is Mycobacterium tuberculosis (including latent or dormant forms) or Mycobacterium leprae. The compositions of the present invention may be particularly suitable for treating Mycobacterium leprae and latent or dormant forms of Mycobacterium tuberculosis. This is described, for example, in Robert Gelber, Koen Andries et al., Antimicrobial Agents and Chemotherapy, Sept 2009, p. 3989-3991 (the contents of which are hereby incorporated by reference and essentially here reported that low-concentration and intermittent dosing of bedaquiline can be expected for leprosy patients; The lowest dose that killed 99% of the bacilli was 30 mg/kg/wk for M. tuberculosis and <5.0 mg for M. lepra /kg/wk, hence once-monthly dosing can be as efficient as five times-weekly dosing; Other publications on efficacy include Antimicrobial Agents and Chemotherapy, by Baohong Ji, Koen Andries et al., April 2006, p.1558-1560)--the contents of which are also hereby incorporated by reference ), because lower concentrations of bedaquiline in plasma may be effective against such infections to treat these particular infections. Therefore, the compositions of the present invention are particularly suitable for methods of treating a subject infected with Mycobacterium leprae, or a latent/dormant form of Mycobacterium tuberculosis. obtain. Such methods of treating subjects infected with pathogenic mycobacteria include administration, by intramuscular or subcutaneous injection, of a therapeutically effective amount of a pharmaceutical composition as specified above or herein below. . Alternatively, the invention may be used for the manufacture of medicaments for treating pathogenic mycobacterial infections (or for the use of such medicaments in certain treatment regimens as described herein). ), relates to the use of a pharmaceutical composition as specified above or hereinbelow. In one embodiment, the composition is for long-term treatment of pathogenic mycobacterial infections. In certain embodiments, the pathogenic mycobacterial infection is as described above or hereinbelow, such as an infection requiring long-term treatment (in a further embodiment, bedaquiline or its active Infections that may be further treated at relatively low plasma concentration levels of metabolites, such as latent/dormant Mycobacterium tuberculosis or, in certain embodiments, Mycobacterium leprae ).

The present invention further relates to methods of treating subjects infected with pathogenic mycobacteria such as Mycobacterium tuberculosis (which also includes multidrug-resistant tuberculosis). The term "drug resistance" (DR) is a term well understood by those skilled in the art of microbiology. Drug-resistant Mycobacterium is no longer susceptible to at least one previously effective drug and has developed the ability to withstand antimicrobial challenge by at least one previously effective drug. It is Mycobacterium. Drug-resistant strains can pass on their ability to tolerate to their offspring. Said resistance can be due to random genetic mutations in the bacterial cell that alter its susceptibility to a single drug or to different drugs. Multidrug-resistant (MDR) tuberculosis is a specific form of drug-resistant tuberculosis due to bacterial resistance (with or without resistance to other drugs) to at least isoniazid and rifampicin, the two most potent anti-TB drugs at present. is. Accordingly, "drug resistance" whenever used herein above or herein below includes multi-drug resistance. Compositions of the invention are also useful in treating MDR-TB.

In another aspect, Mycobacterium tuberculosis, M . M. bovis, M. M. leprae, M. M. avium and M. avium. A method for the long-term treatment of a subject infected with a pathogenic mycobacterium such as M. marinum, said method comprising the method described above or herein below for administration by intramuscular or subcutaneous injection. wherein the composition is administered intermittently at time intervals ranging from 1 week to 1 year, or 1 week to 2 years, or administration A method is provided. Alternatively, or alternatively, the present invention is directed to Mycobacterium tuberculosis, M. tuberculosis. M. bovis, M. M. leprae, M. M. avium and M. avium. For the manufacture of a medicament for the long-term treatment of subjects infected with pathogenic mycobacteria such as M. marinum, for administration by intramuscular or subcutaneous injection, as specified above or herein below. wherein the composition is administered intermittently for periods ranging from 1 week to 1 year, or 1 week to 2 years. Hence, the term "long-term treatment" means that a single dose or administration (e.g., by intramuscular or subcutaneous injection) is administered over a period of time, e.g., hours, weeks, as described herein. or over several months (e.g., in some embodiments, over a period of at least or up to 1 month, 3 months, or 6 months); See In other words, long-term treatment can refer to an extended period of time (as described herein) between doses/administrations, where there are two or more doses/administrations, i.e., intervals are described herein for a long period of time.

In another aspect, long-term treatment of subjects infected with pathogenic mycobacteria (e.g., any of the types as described herein) as described herein (e.g., above). Methods are provided for, wherein one dose or administration (e.g., in an amount described herein, e.g., herein below) is provided/required (and have a sustained effect, eg, over the time periods described herein). In another aspect, two such doses or administrations are provided/required, wherein the doses/administrations are given at intervals, wherein the interval period is as described herein Such long-term treatment regimes are provided, eg, for periods of at least or up to 1 month, 3 months, or up to 6 months—eg, periods of sustained therapeutic effect. In further embodiments, such long-term treatment regimens are provided in which three such doses or administrations are provided/required at intervals as described herein. In yet further embodiments, a lead as described herein but (not a long-term treatment regime, e.g., a course of once-daily dosing lasting 1 week, 2 weeks, 3 weeks or 1 month) A long-term treatment regime is provided, preceded by an in-treatment phase.

The present invention further provides a method for the prevention of pathogenic mycobacterial infections in a subject at risk of contracting a pathogenic mycobacterial infection, said method comprising: A method comprising administering to said subject an amount of a pharmaceutical composition effective to prevent a pathogenic mycobacterial infection, as further specified herein below. Or alternatively, the present invention relates to a method as specified above or herein for the manufacture of a medicament for the prevention of pathogenic mycobacterial infections in subjects at risk of infection with pathogenic mycobacterial infections. with the use of pharmaceutical compositions as further specified below.

In another aspect, the invention provides a method for the long-term prevention of pathogenic mycobacterial infection in a subject at risk of contracting a pathogenic mycobacterial infection, said method comprising: or administering to said subject an effective amount of a pharmaceutical composition as further specified herein below, wherein the composition is administered for 1 week to 1 year, or 1 week to 2 years is or will be administered intermittently at intervals of time within the range of

The present invention further provides a medicament, as specified above or herein, for the manufacture of a medicament for the long-term prevention of pathogenic mycobacterial infections in subjects at risk of infection with pathogenic mycobacterial infections. wherein the composition is administered intermittently at time intervals ranging from 1 week to 1 year or 1 week to 2 years, or will be administered.

In one embodiment, the invention relates to a use or method as specified herein, wherein the pharmaceutical composition is within the range of 1 week to 1 month, or within the range of 1 month to 3 months, or will be administered or will be administered at time intervals within the range of 3 months to 6 months, or within the range of 6 months to 12 months, or within the range of 12 months to 24 months.

In another embodiment, the present invention relates to a use or method as specified herein, wherein the pharmaceutical composition is administered once every two weeks, or once every month, or once every three months. It is administered or will be administered once every day.

Further pharmaceutical compositions, methods of treatment or prophylaxis, and uses for the manufacture of medicaments based on these compositions will be described hereinbelow and are considered part of the present invention. intended.

The invention is also described with reference to the following figures.

PSD measurement results of Reference Example A at time zero and at 1 month, where "Concept 7" means Reference Example A PSD measurements for Reference Examples B and C under various conditions (including after autoclave sterilization), where Concept 3 means Reference Example B and Concept 4 means Reference Example C PSD of the microsuspension of Example 1 before and after autoclaving. PSD of the microsuspension of Example 1 under various conditions, including after autoclaving and after additional time (and at various temperatures) PSD of the microsuspension of Example 1 under various other conditions, including up to 3 months at 60°C "Plasma kinetics of TMC207 in male rats following IM or SC administration of a 200 mg/ml microformulation (see Example 1, Formulation 1B i.e. microsuspension) at a dose of 40 mg/kg" and "Plasma kinetics of TMC207 in male rats following IM or SC administration of a 200 mg/ml nanoformulation (see Example 1, Formulation 1A, i.e., Nanosuspension) at a dose of 40 mg/kg. ” Plasma concentration versus time profiles of subcutaneously administered bedaquiline LAI microsuspensions containing different surfactants (PEG4000 in combination with TPGS, and TGPGS) in rats; data represent means in SD. Plasma concentration versus time profiles of bedaquiline (BDQ) metabolites after subcutaneous administration of BDQ LAI microsuspensions containing different surfactants (PEG4000 in combination with TPGS, and TGPGS) in rats; data are means in SD. represents Plasma concentration versus time profiles of intramuscularly administered bedaquiline LAI microsuspensions containing different surfactants (PEG4000 in combination with TPGS, and TGPGS) in rats; data represent means in SD. Plasma concentration versus time profiles of bedaquiline (BDQ) metabolites after intramuscular administration of BDQ LAI microsuspensions containing different surfactants (PEG4000 in combination with TPGS, and TGPGS) in rats; data are means in SD. represents

The compound used in the present invention is the compound TMC207, also referred to as bedaquiline.

Bedaquiline can be used in its non-salt form or as a suitable pharmaceutically acceptable salt form, such as an acid addition salt form or a base addition salt form. In certain embodiments, bedaquiline is in its non-salt form in the compositions of the invention.

Pharmaceutically acceptable acid addition salts are defined to include the therapeutically active, non-toxic acid addition salt forms that bedaquiline is able to form. Said acid addition salts convert bedaquiline in its free form to a suitable acid, such as inorganic acids such as hydrohalic acids, especially hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; organic acids such as acetic acid, Hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfone It can be obtained by treatment with acid, cyclamic acid, salicylic acid, p-aminosalicylic acid and pamonic acid. Fumarate is conceivable, especially given that it is the form used in the already marketed product Sirturo®.

Potential therapeutically active non-toxic base addition salt forms can be prepared by treatment with suitable organic and inorganic bases. Suitable base salt forms are, for example, the ammonium, alkali metal and alkaline earth metal salts, especially the lithium, sodium, potassium, magnesium and calcium salts, salts with organic bases such as the benzathine salt, N-methyl-D-glucamine salts, hibramine salts, and salts with amino acids such as arginine and lysine.

Conversely, said acid or base addition salt forms can be converted to the free form by treatment with a suitable base or acid.

The term "addition salt" as used in the framework of this application also includes the solvates that bedaquiline as well as salts thereof are able to form. Such solvates are, for example, hydrates and alcoholates.

Whenever reference to bedaquiline (or TMC207) is used herein, used in the commercial product Sirturo® and disclosed as an anti-mycobacterial agent in WO 2004/011436, Refers to a single stereoisomer.

The physicochemical properties of bedaquiline have unique pharmacokinetic properties in that they can be used for long-term treatment of pathogenic mycobacterial infections as well as for long-term prevention of pathogenic mycobacterial infections. It has been found that it is possible to produce micro- or nanoparticle suspensions and only a limited number of drug administrations are required for this purpose. This is beneficial in terms of pill load as well as patient compliance with a given dosing regime.

As used herein, the term "treating a pathogenic mycobacterial infection" relates to treating a subject infected with a pathogenic mycobacterial infection. Such a mycobacterial infection may be mycobacterial tuberculosis or multi-drug resistant mycobacterial tuberculosis.

The term "prevention of pathogenic mycobacterial infection" relates to preventing or avoiding a subject from becoming infected with a pathogenic mycobacterial infection. The source of infection can vary, such as, for example, material containing pathogenic mycobacterial infections.

The terms "therapeutically effective amount," "an amount effective to prevent pathogenic mycobacterial infections," and like terms refer to the amount or concentration (or The amount/concentration of the active ingredient bedaquiline in such compositions). By "effective plasma concentration" is meant a plasma concentration of bedaquiline that provides effective treatment or effective prevention of pathogenic mycobacterial infections. This is because a given amount/dose/administration can be associated with a desired exposure concentration or desired plasma concentration for effective treatment/prevention, e.g., as described herein. (See, eg, Examples).

The term "subject" specifically relates to humans.

The term "micro- or nanoparticle" refers to particles in the micrometer or nanometer range. The size of the particles should be less than the maximum size, above which administration by subcutaneous or intramuscular injection becomes impaired or even no longer possible. Said maximum dimension depends, for example, on limitations imposed by the diameter of the needle or by the body's rejection of large particles, or both. In one embodiment, the pharmaceutical composition of the invention comprises bedaquiline in microparticle form. In another embodiment, the pharmaceutical composition of the invention comprises bedaquiline in nanoparticulate form.

The average effective particle size of the micro- or nanoparticles of the present invention is less than about 50 μm, or less than about 20 μm, or less than about 10 μm, or less than about 1000 nm, or less than about 500 nm, or less than about 400 nm, or less than about 300 nm, or less than about It can be less than 200 nm. The lower limit for the average effective particle size may be as low as, for example, about 100 nm, or about 50 nm. In one embodiment, the average effective particle size is from about 50 nm to about 50 μm, or from about 50 nm to about 20 μm, or from about 50 nm to about 10 μm, or from about 50 nm to about 1000 nm, from about 50 nm to about 500 nm, or from about 50 nm to about 400 nm. or in the range of about 50 nm to about 300 nm, or about 50 nm to about 250 nm, or about 100 nm to about 250 nm, or about 150 nm to about 220 nm, or 100 to 200 nm, or about 150 nm to about 200 nm, such as about 130 nm, or about 150 nm. For example, both after preparation and after a period of up to 3 months (e.g., when stored at temperatures of about 5°C, 25°C, and 40°C), generally:
- Microsuspensions, in certain embodiments, may have a D90 of about 3-10 μm (eg, 3.5, 4, or 5 μm) and a D50 of about 2-4 μm (eg, about 3 μm) - Nanosuspensions The turbidity, in certain embodiments, has a D90 of about 0.5-1.5 μm (eg, about 1 μm or less, or about 1000 nm or less) and about 0.1-0.5 μm (eg, about 0.3 μm or less, or less than about 300 nm).

In some embodiments, microparticles are used, wherein the average effective particle size, as measured by D10, D50 and/or D90 (as measured by D50 in some embodiments) is less than about 50 μm , or less than about 20 μm and greater than about 0.1 μm (100 nm). In some embodiments, the range for such microparticles used in the compositions of the present invention is from about 20 μm to about 0.1 μm (in further embodiments, from about 15 μm to greater than 0.2 μm (200 nm); In embodiments, from about 10 μm to greater than about 0.5 μm (500 nm), such as from about 10 μm to about 1 μm or greater than about 1000 nm, or greater than about 500 nm, or greater than about 400 nm, or greater than about 300 nm, or greater than about 200 nm. The foregoing values refer to post-preparation measurements, however, they are also, in certain embodiments, after a period of up to 3 months (e.g., 5 days, 1 week, 2 weeks, 1 month, 2 months, or after 3 months) and after storage at various temperatures (eg, at temperatures of about 5°C, 25°C and 40°C).

As used herein, the term average effective particle size has its conventional meaning as known to those skilled in the art, e.g. It can be measured by a particle size measurement technique known in the technical field such as. The average effective particle size mentioned herein can be related to the volume distribution of the particles. In that case, "effective average particle size less than about 50 μm" means that at least 50% of the volume of the particles has a particle size less than 50 μm effective average size, the same applies to other effective particle sizes mentioned. It also applies to Similarly, the average effective particle size can be related to the weight distribution of the particles, but usually this will result in the same or nearly the same value for the average effective particle size.

The pharmaceutical compositions of the present invention provide release of the active ingredient bedaquiline over an extended period of time, therefore they can also be referred to as sustained release or delayed release compositions. After administration, the composition of the present invention remains in the body and releases bedaquiline continuously and maintains such concentrations of this active ingredient in the patient's system for a long period of time, thereby preventing pathogenic mycobacteria during said period of time. Provide appropriate treatment or prevention of infectious diseases. The pharmaceutical compositions of the present invention are said to remain in the body and continuously release bedaquiline (and its active metabolite, referred to herein as M2; see herein below methyl-substituted metabolites). Due to the fact they can be said to be pharmaceutical compositions suitable as long-acting (or depot) formulations.

As used herein, the term "long term" refers to a time (or period) that can range from 1 week up to 1 year or up to 2 years, or 1 to 2 weeks, or 2 ~3 weeks, or a period within the range of 3 to 4 weeks, or 1 to 2 months, or 2 to 3 months, or 3 to 4 months, or 3 to 6 months, or 6 to 12 months, or 12 to 24 months or days, such as 7, 10 or 12 days, or weeks, such as 2, 3 or 4 weeks, or 1 month, or months, such as 2, 3, 4, 5 or 6 months, or Even longer means a period of time which can be in the range of, for example, 7, 8, 9 or 12 months.

The pharmaceutical compositions of the invention may be applied in the long-term treatment or long-term prophylaxis of pathogenic mycobacterial infections, or in other words they may be used for long-term treatment of pathogenic mycobacterial infections or pathogenic mycobacterial infections. It can be used to prevent mycobacterial infections. The compositions of the present invention are effective in treating or preventing pathogenic mycobacterial infections for extended periods of time, such as at least about one week or more, or about one month or more. The expression "effective for at least about one week" means that the plasma concentration of the active ingredient bedaquiline (and/or its active metabolite M2) should exceed a threshold value. For therapeutic use, the threshold is the lowest plasma concentration at which bedaquiline (and/or its active metabolite M2) provides effective treatment of pathogenic mycobacterial infections. For applications in the prevention of pathogenic mycobacterial infections, said threshold is the lowest plasma concentration at which bedaquiline (and/or its active metabolite M2) is effective in preventing transmission of pathogenic mycobacterial infections. be.

For example, "long-term prevention of pathogenic mycobacterial infections" or "long-term treatment of pathogenic mycobacterial infections", or "long-term" as used in connection with similar terminology, from one week up to one year. means a period of time which may be up to or up to 2 years or longer, for example in the range of 5 or 10 years. Especially in the case of treatment of pathogenic mycobacterial infections, such periods may be long, from about one month to several months, up to a year or even longer. Such periods may also be relatively short, particularly for prophylaxis. Shorter periods may be several days, such as 7, 10 or 12 days, or weeks, such as 2, 3 or 4 weeks, or 1 month, or months, such as 2, 3, 4, 5 or 6 months or even more. For example, 7, 8, 9 or 12 months old. In one embodiment, the methods and uses according to the invention are administered over a period of one month, or several months, such as 2, 3, 4, 5 or 6 months or even more, such as 7, 8, 9 or 12 months. , for the prevention of pathogenic mycobacterial infections.

The pharmaceutical composition of the invention can be administered at various time intervals. When used to prevent pathogenic mycobacterial infections, the pharmaceutical compositions of the invention can be administered only once or a limited number of times, such as 2, 3, 4, 5 or 6 times, or more. can. This may be recommended when prophylaxis is required for a limited period of time, such as during periods when there is risk of infection.

The pharmaceutical composition of the present invention can be administered at the time intervals described above, for example within the range of 1 week to 1 month, or within the range of 1 month to 3 months, or within the range of 3 months to 6 months, or within the range of 6 months to 12 months. can be administered at intervals such as those within the range of In one embodiment, the pharmaceutical composition can be administered once every two weeks, or once every month, or once every three months. In another embodiment, the time interval is in the range of 1-2 weeks, or 2-3 weeks, or 3-4 weeks, or the time interval is 1-2 months, or 2-3 months, or 3-4 months, or 3-6 months, or 6-12 months, or 12-24 months. The time interval can be at least one week, but can also be several weeks, such as 2, 3, 4, 5 or 6 weeks, or one month, or several months, such as 2, 3, 4, 5 or It can be a time interval of 6 months or even longer, for example 7, 8, 9 or 12 months. In one embodiment, the pharmaceutical compositions of the invention are administered at time intervals of 1, 2 or 3 months. These longer periods between each administration of the pharmaceutical compositions of the invention provide further improvements in terms of pill load and compliance. To further improve compliance, the medications may be taken on a particular day of the week if the composition is administered on a weekly schedule, or on a particular day of the month if the composition is administered on a monthly schedule. The patient can be instructed to

The length of time interval between each administration of the composition of the invention can vary. For example, the time interval may be selected as a function of plasma concentration. If the plasma concentrations of bedaquiline (and/or its active metabolite M2) are considered too low, e.g. if they approach the minimum plasma concentrations specified herein below, this interval may be shorter. good. This interval may be longer if the plasma concentration of bedaquiline (and/or its active metabolite M2) is considered too high. In one embodiment, the compositions of the invention are administered at equal time intervals. The composition may be administered without any intermediate additional administrations, or in other words, the composition may be administered for varying or equal lengths of time, such as a period of at least one week, or any of the doses specified herein. may be administered at specific time points apart from each other for other periods of time, during which no additional bedaquiline is administered. Time intervals of the same length have the advantage that the dosing schedule is simple, eg dosing takes place on the same day of the week or on the same day of the month. Such a dosing schedule therefore entails a limited "pill load", thereby beneficially contributing to patient compliance with the prescribed dosing regime.

Its concentration (or "C") in the plasma of subjects treated with bedaquiline (and/or its active metabolite M2) is generally measured in mass per unit volume, typically nanograms per milliliter (ng/ ml). For convenience, this concentration may be referred to herein as the "plasma drug concentration" or "plasma concentration."

The dose (or amount) of bedaquiline administered depends on the amount of bedaquiline in the pharmaceutical composition of the invention or on the amount of a given composition administered. If higher plasma concentrations are desired, either higher bedaquiline concentration compositions or higher amounts of a given composition, or both, may be administered. The opposite is true if lower plasma concentrations are desired. Combinations of different time intervals and different dosages may also be selected to obtain certain desired plasma concentrations.

The dose (or amount) of bedaquiline administered also depends on the frequency of administration (ie, the time interval between each administration). Generally, the dose will be higher if the administration is less frequent. All these parameters can be used to target plasma concentrations to desired values.

The dosing regime also depends on whether prophylaxis of pathogenic mycobacterial infections or treatment of pathogenic mycobacterial infections is envisaged. For treatment, the dose of bedaquiline administered, or the frequency of dosing, or both, is selected to keep the plasma concentration of bedaquiline above the minimum plasma concentration. In this context, the term "minimum plasma concentration" (or _Cmin ) refers to the plasma concentration of bedaquiline (and/or its active metabolite M2) that provides effective treatment of pathogenic mycobacterial infections. . In particular, the plasma concentration of bedaquiline (and/or its active metabolite M2) is less than a minimum plasma concentration of about 10 ng/ml, or greater than about 15 ng/ml, or greater than about 20 ng/ml, or greater than about 40 ng/ml. is kept at a higher level. Plasma concentrations of bedaquiline (and/or its active metabolite M2) are higher, e.g., greater than about 50 ng/ml, or greater than about 90 ng/ml, or greater than about 270 ng/ml, or greater than about 540 ng/ml It can be kept above the minimum plasma concentration. In one embodiment, the plasma concentration of bedaquiline (and/or its active metabolite M2) is maintained above a concentration of about 13.5 ng/ml or maintained above a concentration of about 20 ng/ml. be Alternatively, the plasma concentration of bedaquiline (and/or its active metabolite M2) is within a range, in particular starting from a minimum plasma concentration selected from the above values, to a higher plasma concentration selected from the above values. ending in moderate concentrations and between 500 ng/ml and 1000 ng/ml (such as 10-15, 10-20, 10-40, or 15-20, or 15-40, or 15-90, etc., or 20-40, 20 to 90, or 20 to 270, etc., or 40 to 90, 40 to 270, or 40 to 540, etc. (each time from about the indicated value in ng/ml to about the indicated value in ng/ml) In one embodiment, the ranges are from about 10 to about 20, from about 20 to about 90, from 90 to 270, from 270 to 540, from 540 to 1000 (each time about the indicated value in ng/ml). to about the indicated value in ng/ml).

Plasma concentrations of bedaquiline (and/or its active metabolite M2), since at lower concentrations the bacteria can no longer be adequately suppressed and consequently may multiply with the added risk of mutation emergence. should be kept above the minimum plasma concentration mentioned above.

In the case of prophylaxis, the term "minimum plasma concentration" (or _Cmin ) refers to the lowest plasma concentration of bedaquiline (and/or its active metabolite M2) that provides effective treatment/prevention of infection.

In particular, in the case of prophylaxis, the plasma concentration of bedaquiline (and/or its active metabolite M2) can be kept above the minimum plasma concentration mentioned above for treatment. However, in prophylaxis, plasma levels of bedaquiline (and/or its active metabolite M2) can be kept at lower levels, such as about 4 ng/ml, or about 5 ng/ml, or greater than about 8 ng/ml. can. Plasma concentrations of bedaquiline (and/or its active metabolite M2) preferably are should be kept above the minimum plasma concentration of Plasma concentrations of bedaquiline (and/or its active metabolite M2) may be kept at slightly higher concentrations to have a margin of safety. Such higher concentrations start at about 50 ng/ml or higher. Plasma concentrations of bedaquiline (and/or its active metabolite M2) are within the ranges described above in relation to therapy, but with a lower limit of about 4 ng/ml, or about 5 ng/ml, or about 8 ng/ml. Concentrations including plasma concentrations of ml can be maintained.

An advantage of bedaquiline (and/or its active metabolite M2) is that it can be used up to relatively high plasma concentrations without any significant side effects. Plasma concentrations of bedaquiline (and/or its active metabolite M2) can reach relatively high concentrations, but as with any drug, bedaquiline (and/or its active metabolite M2) can cause significant side effects in plasma. The maximum plasma concentration (or C _max ), which is the concentration, should not be exceeded. Moreover, tissue release of the compound, which is not counted within the plasma concentration, should also be taken into account. As used herein, the term "major side effect" means that a side effect is present in the relevant patient population to the extent that it affects the patient's normal functioning. In certain embodiments, the amount and frequency of administration of bedaquiline (and/or its active metabolite M2) administered is such that the plasma concentration is between the maximum plasma concentration (or C _max as specified above) and the minimum plasma It is chosen to be kept at a concentration comprised between the medium concentration (or C _min as specified above) over an extended period of time.

Keeping plasma concentrations of bedaquiline (and/or its active metabolite M2) at relatively low concentrations, such as, in certain cases, as close as possible to the minimum plasma concentrations specified herein. may be desirable. This allows the frequency of administration and/or the amount of bedaquiline (and/or its active metabolite M2) administered at each administration to be reduced. It also makes it possible to avoid unwanted side effects, which may contribute to the acceptance of the dosage form in most of the target population groups, which are healthy individuals at risk of infection and therefore less prone to endure side effects. deaf. Plasma concentrations of bedaquiline (and/or its active metabolite M2) can be kept relatively low in the case of prophylaxis. One embodiment relates to a use or method, as specified above or herein below, for the prevention of infectious diseases, wherein bedaquiline (and/or its active metabolite M2) Plasma concentrations are as specified herein, and the maximum plasma concentration is approximately equal to the lowest plasma concentration at which the active ingredient is therapeutically operative, also as specified herein.

In another embodiment, bedaquiline (and/or its active metabolite M2) has a plasma concentration of about 10 ng/ml, more particularly about 15 ng/ml, even more particularly 20 ng/ml, even more particularly about 40 ng/ml, Concentrations below the lower maximum plasma concentration are maintained. In certain embodiments, the plasma concentration of bedaquiline (and/or its active metabolite M2) is kept below a concentration of about 13.5 ng/ml. In one embodiment, the plasma concentration of bedaquiline (and/or its active metabolite M2) is within the interval between the lower maximum blood concentration specified above and the minimum plasma concentration mentioned in relation to prophylaxis. kept in For example, the plasma concentration of bedaquiline (and/or its active metabolite M2) is kept below about 10 ng/ml and above a minimum concentration of about 4 ng/ml.

In other cases, e.g., when there is a high risk of infection and more frequent and/or higher dosing is not a problem, keeping plasma levels of bedaquiline (and/or its active metabolite M2) at relatively high levels. may be desirable. In these cases, the minimum plasma concentration is the lowest plasma concentration of bedaquiline (and/or its active metabolite M2) that provides effective treatment of pathogenic mycobacterial infections, such as the specific concentrations described herein. May be equal to medium concentration.

For prophylaxis, doses to be administered are from about 0.2 mg/day to about 50 mg/day, or from about 0.5 mg/day to about 50 mg/day, or from about 1 mg/day to about 10 mg/day, or about 2 mg/day. /day to about 5 mg/day, such as about 3 mg/day. This is a weekly dose of about 1.5 mg to about 350 mg, especially about 3.5 mg to about 350 mg, especially about 7 mg to about 70 mg, or about 14 mg to about 35 mg, such as about 35 mg, or about 6 mg to about 3000 mg, especially corresponding to a monthly dose of about 15 mg to about 1,500 mg, more particularly about 30 mg to about 300 mg, or about 60 mg to about 150 mg, eg about 150 mg. Dosages for other dosing regimens can be readily calculated by multiplying the daily dose by the number of days between each administration.

For therapy, the dose to be administered should be somewhat higher, from about 1 mg/day to about 150 mg/day, or from about 2 mg/day to about 100 mg/day, or from about 5 mg/day to about 50 mg/day. daily, or from about 10 mg/day to about 25 mg/day, such as about 15 mg/day. Corresponding weekly or monthly doses can be calculated as described above. For prophylactic applications, the same dosages may be used as for therapeutic applications, although lower doses may be used. In certain embodiments, doses/administrations are given at monthly intervals, or at 3-month or 6-month intervals, with a total duration of treatment of 3, 6, or 12 months. When the dose/administration is once a month, once every three months, or once every six months, in certain embodiments a given dose (e.g., in a human subject) is given for two weeks. calculated based on the 400 mg daily dose taken. Thus, the total amount of bedaquiline given per dose may be about 5600 mg (eg within the range of 3000-8000 mg), although it may be up to ⅕ of such amount (eg 500 and 2000 mg, eg about 1000-1500 mg).

In another embodiment, for prophylactic or particularly therapeutic cases, doses can also be expressed in units of mg/kg. For example, in the Examples, certain doses can be administered on a weight basis (eg, in mammals, and, as shown in the Examples herein, in mice), thus 1 mg/kg to 1000 mg/kg. of 40 mg/kg, 80 mg/kg, 160 mg/kg, 320 mg/kg or 480 mg/kg may be used, such doses being effective for 4, 8 or 12 weeks. can continue (eg as shown in the examples). For example, one dose may be taken every 4 weeks (seen as a substantially 12-week treatment regimen, i.e., 3 total doses), or as may be evidenced by monitoring over a 12-week period. A single dose that substantially provides adequate therapy (eg, as defined by a reduction in CFU, see Examples) may be taken. Thus, in certain embodiments, a single dose may be taken (eg, 1 mg/kg to 1000 mg/kg, such as 2 mg/kg to 500 mg/kg), or a single dose thereof, to treat a bacterial infection. Such doses may be taken every 4 weeks (eg 2 or 3 such doses may be taken). Such dosage depends on the bacterial infection to be treated. For example, in the treatment of latent tuberculosis or leprosy, lower doses are required (e.g., compared to multidrug-resistant tuberculosis), given that lower amounts of bedaquiline are required to control the bacteria. may occur. It has been shown in mice that a single dose of 160 mg/kg can sufficiently reduce CFU in a mouse model of latent tuberculosis infection, an example of which can be described herein below. - In addition, it was also seen that 2 or 3 doses of 160 mg/kg (2nd and 3rd doses administered at 4 and 8 weeks respectively) were also effective in this model.

It has been found that once administered, plasma concentrations of bedaquiline (and/or its active metabolite M2) are more or less stable, ie they fluctuate within defined limits. Plasma concentrations are found to more or less approach a steady-state mode, or to a zero-order release rate for extended periods of time. By "steady state" is meant the state in which the amount of drug present in the plasma of a subject remains at more or less the same concentration over an extended period of time. Plasma concentrations of bedaquiline (and/or its active metabolite M2) generally do not show any decline below the minimum plasma concentration at which the drug is effective. The term "remaining at more or less the same concentration" refers to small variations in plasma concentration within an acceptable range, such as about ±30%, or about ±20%, or about ±10%, or about ±10% does not exclude that there may be variations within

In some cases, there may be an initial plasma concentration peak after administration, after which plasma concentrations reach "steady state" as described herein below.

The compositions of the invention exhibit good local tolerance and ease of administration. Good local tolerance is associated with minimal irritation and inflammation at the site of injection; ease of administration refers to the needle size and length of time required to administer a dose of a particular drug formulation. . Additionally, the compositions of the present invention exhibit good stability and have acceptable shelf life.

The micro- or nanoparticles of the present invention have a surface-modifying agent adsorbed onto their surface. The function of surface modifiers is to act as wetting agents as well as stabilizers for colloidal suspensions.

In one embodiment, the micro- or nanoparticles in the composition of the present invention predominantly comprise crystalline bedaquiline or a salt thereof; and a surface-modifying agent, in a total amount of at least about 50% of the micro- or nanoparticles , or at least about 80%, or at least about 90%, or at least about 95%, or at least about 99%. As provided herein, in certain embodiments bedaquiline is in its non-salt form (i.e., in its "free form"), and in further embodiments it is in its crystalline non-salt (i.e., free) form. It is in. In this regard, as mentioned herein, bedaquiline is described in WO2004/011436 (or in WO2006/125769, which describes optical resolution using chiral reagents). can be prepared as such using the procedures described in According to such procedure bedaquiline is obtained by precipitation from toluene/ethanol and the product is shown to crystallize. Such forms of bedaquiline can be used in the preparation of the compositions of the present invention and further such forms are characterized by:
(i) A DSC curve showing a melting endotherm at 181.5° C. (endotherm onset) and melting of the product at about 182.5° C. (immediately followed by decomposition; Compound migration was measured by differential scanning calorimetry (DSC), the sample pan was closed with a suitable core and the following parameters were used: initial temperature 25°C; heating range 10°C/min; final temperature 300°C. DSC curves are recorded on a TA-Instruments Q2000 MTDSC equipped with an RCS cooling unit using a nitrogen flow rate of 50 ml/min);
(ii) infrared (IR) spectral peaks at about 1600 cm ⁻¹ , about 1450 cm ⁻¹ , about 1400 cm ⁻¹ , about 1340 cm ⁻¹ , and about 1250 cm ⁻¹ among others (where the sample was scanned at 32 scans, 1 cm ⁻¹ resolution A Thermo Nexus 670 FTIR spectrometer, a DTGS detector with a KBr window, a Ge beamsplitter on KBr and a micro ATR accessory (Harrick Split Pea with Si crystals) for analysis) and/or (iii) about 11.25° 2-theta, about 18° 2-theta, about 18.5° 2-theta, showing diffraction peaks in the absence of a halo indicative of the crystallinity of the product, about 19° 2-theta, about 20.25° 2-theta, about 21.25° 2-theta, about 22.25° 2-theta, about 24.5° 2-theta and about 27° 2-theta. X-ray powder diffraction (XRPD) with characteristic peaks, where the analysis was performed on a PANalytical (Philips) X'PertPRO MPD diffractometer, equipped with a Cu LFF X-ray tube, and the compound was laid out on a zero background sample holder; instrument parameters were: generator voltage - 45 kV; generator amperage - 40 mA; geometry - Bragg-Brentano; stage - spinner stage; scan mode - continuous; Scan range 3-50° 2θ; step size 0.02°/step; counting time 30 sec/step; spinner decomposition time -1 sec;
It can be a single crystalline polymorph with

Thus, in certain embodiments, the bedaquiline (i.e., prior to conversion to micro/nanoparticles) used in the process for preparing the compositions of the present invention is in a crystalline form (e.g., the specific of the form ). In a further embodiment of the present invention, the bedaquiline (i.e., after conversion to micro/nanoparticulates, e.g., by milling) used in the compositions of the present invention is also in crystalline form (e.g., characterized above in a particular form).

In a further aspect, the present invention is a pharmaceutical composition for administration by intramuscular or subcutaneous injection, comprising a therapeutically effective amount of bedaquiline, or a pharmaceutically acceptable salt thereof, in the form of a suspension of particles. There is
(1) bedaquiline, or a pharmaceutically acceptable salt thereof, in micro- or nanoparticulate form, having a surface-modifying agent adsorbed to its surface;
(2) consisting essentially of a pharmaceutically acceptable aqueous carrier; wherein the active ingredient is suspended;
The present invention relates to a pharmaceutical composition characterized in that the surface modifier contains PEG4000 or the like.

The formulations of the present invention are shown to contain PEG 4000 (etc.), which for the avoidance of doubt may be in combination with another suitable surface modifier.

Suitable surface modifiers (which may be used in combination with PEG 4000 and the like) can be selected from known organic and inorganic pharmaceutical excipients such as various polymers, low molecular weight oligomers, natural products and surfactants. . Particular surface modifiers include nonionic and anionic surfactants. Representative examples of surface modifiers include gelatin, casein, lecithin, salts of negatively charged phospholipids or their acid forms (phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phosphatic acid, and alkali metal salts such as sodium salts thereof, e.g. egg phosphatidylglycerol sodium, such as the product available under the trade name Lipoid™ EPG), acacia gum, stearic acid, benzalkonium chloride, polyoxyethylene alkyl ethers, e.g. , macrogol ethers such as cetomacrogol 1000, polyoxyethylene castor oil derivatives; polyoxyethylene stearate, colloidal silicon dioxide, sodium dodecyl sulfate, sodium carboxymethylcellulose, sodium taurocholate, sodium desoxytaurocholate, desoxycholic acid Bile salts such as sodium; methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl-methylcellulose, magnesium aluminosilicate, polyvinyl alcohol (PVA), Pluronic™ F68, F108, block copolymers of ethylene oxide and propylene oxide, and poloxamers, such as F127; tyloxapol; vitamin E-TGPS (α-tocopheryl polyethylene glycol succinate, especially α-tocopheryl polyethylene glycol 1000 succinate); tetrafunctionality derived from the sequential addition of ethylene oxide and propylene oxide to ethylenediamine. dextrans; lecithin; dioctyl esters of sodium sulfosuccinate, such as products sold under the trade name Aerosol OT™ (AOT); sodium lauryl sulfate ( Duponol™ P); alkylaryl polyether sulfonates available under the trade name Triton™ X-200; polyoxyethylene sorbitan fatty acid esters (Tweens™ 20, 40, 60 and 80); sorbitan esters of fatty acids. (Span™ 20, 40, 60 and 80 or Arlacel™ 20, 40, 60 and 80); hexyldecyltrimethylammonium chloride CTAC); polyvinylpyrrolidone (PVP). If desired, two or more surface modifiers can be used in combination (with PEG 4000, etc.).

Particular surface modifiers that may be used in combination with PEG 4000 (etc.) are selected from poloxamers, α-tocopheryl polyethylene glycol succinates, polyoxyethylene sorbitan fatty acid esters, and salts of negatively charged phospholipids or acid forms thereof. be done. More particularly, the surface modifier is selected from Pluronic™ F108, Vitamin E TPGS, Tween™ 80, and Lipoid™ EPG (in certain embodiments it is Vitamin E TGPS). One or more of these surface modifiers can be used. Pluronic™ F108 corresponds to Poloxamer 338 and generally has the formula HO—[CH ₂ CH ₂ O] _x —[CH(CH ₃ )CH ₂ O] _y —[CH ₂ CH ₂ O] _z —H( wherein the average values of x, y and z are 128, 54 and 128 respectively). Other trade names for poloxamer 338 are Hodag Nonionic™ 1108-F and Synperonic™ PE/F108. In one embodiment, the surface modifier comprises a combination of polyoxyethylene sorbitan fatty acid ester and a phosphatidylglycerol salt (particularly egg phosphatidylglycerol sodium).

The optimum relative amount of bedaquiline to surface modifier is determined by the surface modifier selected, the average effective particle size and the bedaquiline concentration, the specific surface area of the bedaquiline suspension, if it forms micelles, the surface modifier depends on the critical micelle concentration of The relative amount (w/w) of bedaquiline to surface modifier is preferably in the range 1:2 to about 20:1, especially in the range 1:1 to about 10:1, for example 2:1 to about in the range of 10:1, such as about 4:1.

As shown, the surface modifier contains PEG 4000, but may also contain additional surface modifiers such as those previously described herein. In various embodiments of the present invention, the compositions of the present invention have the following w/w ratio:
- at least 1:10 PEG 4000: one or more other surface modifiers - 1:10 to 100:1 (eg about 1:10 to 20:1) PEG 4000: one or more other surface modifiers - PEG 4000 at about 10:1: one or more other surface modifiers containing PEG 4000 and one or more other surface modifiers.

Hence, when the surface modifier of the composition of the present invention comprises at least 1:10 w/w PEG 4000 (or the like): one or more other surface modifiers, it contains 5 mg/mL PEG 4000 and 50 mg/ml of one or more other surface modifiers (eg, Vitamin E TPGS, also referred to herein simply as "TPGS"). Given that in certain embodiments, the relative amount of bedaquiline to surface modifier can be from 1:1 to 10:1 (eg, about 4:1), bedaquiline is about 200 mg/ml in such cases. (which may form a particular injectable formulation or dose). The compositions herein are distinguished because they contain PEG 4000 (and the like) and it can be in relatively small amounts, but in certain embodiments the surface modifier is at least 25% by weight, such as at least 50% by weight of PEG 4000 or the like (the remainder being one or more other suitable surface modifiers such as Vitamin E TPGS as described herein). For example, in some embodiments, the surface modifiers of the compositions of the present invention comprise at least a 1:1 w/w ratio of PEG 4000, etc.:one or more other suitable surface modifiers. In a further embodiment, the surface modifier comprises at least 75% by weight of PEG 4000 or the like, with the balance being one or more suitable surface modifiers as described herein, such as Vitamin E TPGS. be). Thus, in certain embodiments, the surface modifier of the compositions of the present invention comprises at least a 3:1 w/w ratio of PEG 4000 or the like to one or more other suitable surface modifiers. In still further embodiments, the surface modifier of the composition of the present invention comprises at least 85% by weight of PEG 4000, etc., or from about 85% to about 95% of PEG 4000, etc. (in each case, the balance is one or more suitable surface modifiers as described herein, such as Vitamin E TPGS). Thus, in certain embodiments, the surface modifiers of the compositions of the present invention comprise a ratio of at least 8:1 w/w of PEG 4000 or the like to one or more other suitable surface modifiers (e.g., 8:1). ~12:1 w/w ratio of PEG 4000, etc.:one or more other suitable surface modifiers).

The ratio of PEG 4000 (etc.) to one or more other surface modifiers is also dependent on the other surface modifiers being used; When including TPGS and/or Tween (polyoxyethylene polyether sulfonate), the ratios described above may be applicable herein, for example the surface modifier is at least 60% by weight, in embodiments at least 75% % PEG 4000; when the one or more other surface modifiers comprise a poloxamer, the ratio is (of PEG:one or more other surface modifiers) 1:10 to 10:1, such as 1 :5 to 5:1, in embodiments 1:2 to 2:1, in embodiments where the surface modifier is at least 30%, such as at least 40% (and in particular about 50%) of PEG 4000. In some cases, such as when the one or more other surface modifiers are poloxamers, at least 10% PEG 4000 is required, but the upper limit can be 60%.

As indicated, the compositions of the invention include a surface modifier containing PEG 4000 and the like. In some embodiments, the surface modifier can consist essentially of PEG4000 and the like. However, in alternate embodiments, the surface modifier also contains another suitable surface modifier as described herein.

When one or more other surface modifiers are used in the compositions of the present invention, those other surface modifiers may be selected from vitamin E TPGS or poloxamers in certain embodiments. For example, another surface modifier can be Vitamin E TPGS. Hence, as indicated herein, the w/w ratio of bedaquiline to surface modifier can be in the range 2:1 to 10:1 (eg, at about 4:1), hence 200 mg/ If 1 ml of bedaquiline is used (eg for a single injectable dose), it may contain 100 mg/ml to 20 mg/ml of surface modifier. In this case, again indicated, the amount of surface modifier comprises PEG 4000 (etc.) and one or more other suitable surface modifiers, for example, in a ratio of at least 3:1 (i.e., at least PEG 4000) at 75% by weight. Thus, if 100 mg/ml of surface modifier is present, it may consist of at least 75 mg/ml of PEG 4000 or the like, with any remainder being one or more other suitable surface modifiers such as vitamin E TPGS), and when 20 mg/ml of surface modifier is present, it may consist of at least 15 mg/ml of PEG 4000, etc., with any remainder consisting of one or more other suitable surface modifiers. . When 200 mg/ml of bedaquiline is present (e.g., as one injectable dose), when the ratio of bedaquiline to surface modifier can be about 4:1, as indicated herein above, The amount of surface-modifying agent is about 35 mg/ml to 60 mg/ml (eg, about 55 mg/ml, where the surface-modifying agent is about 50 mg/ml of PEG 4000, etc., and about 5 mg/ml of one or more other surface modifiers such as Vitamin E TPGS).

Compositions of the invention may need to be sterilized so that they can be administered to a patient. Achieving sterile compositions can be accomplished in a number of ways, including manufacturing such compositions in an aseptic process or environment. However, such methods have many drawbacks, challenges and are associated with higher costs. A preferred alternative is to undergo sterilization without having to follow a full aseptic process; heat sterilization, autoclaving and gamma irradiation are sterilization steps that can accomplish this. Advantageously, the compositions of the present invention are autoclavable, ie, autoclavable and can be done without substantial deterioration or decomposition of the composition.

Additional challenges appear after sterilization, which include the desired stability of long-acting formulations, undesired aggregation of particles of the active pharmaceutical ingredient (API) within the formulation, and (after sterilization, e.g., autoclaving) ) is related to the desired resuspendability of the formulation.

Although in this case the cloud point may be below the temperature at which autoclaving is performed, the compositions of the invention may be sterilized by, for example, heat sterilization, autoclaving or gamma irradiation (in some embodiments sterilization is autoclaving). sterilization). Advantageously, the compositions of the invention can be easily resuspended after sterilization (even though the cloud point is exceeded during the sterilization process, especially the autoclaving process).

Hence, in a further aspect of the invention,
(a) processes for sterilizing the compositions of the invention (e.g., autoclaving the compositions);
(b) A subsequent process of resuspending such compositions of the invention is provided, which process may be referred to as the "process of the invention". The examples show that PEG 4000 is key in resuspension. It will be appreciated that after sterilization (e.g. heat sterilization or autoclave sterilization) there may be some particle agglomeration, especially if the sterilization process is performed at temperatures above the cloud point, e.g. due to phase separation. . Given that the compositions of the present invention should be suspensions in nature, a resuspension step may be necessary (such resuspension steps may also be used at a later time, e.g. suspension is being prepared for its final use). The composition of the present invention begins as a suspension of bedaquiline particles suspended in a pharmaceutically acceptable carrier, containing a surface modifier (i.e. PEG 4000 as defined herein above). surface modifiers) can be adsorbed onto the surface of bedaquiline and after autoclaving, dissociation between the surface modifiers (also referred to herein as wetting agents) and bedaquiline and/or bedaquiline particle aggregates. can be. Resuspension back to the original suspension is therefore essential and can be accomplished by swirling or shaking the composition of the invention (after sterilization, eg autoclaving). Resuspension (of bedaquiline in the carrier) can occur by adsorbing a surface modifier (ie, PEG 4000 and one or more other suitable surface modifiers) onto the surface of bedaquiline.

As indicated, resuspendability after sterilization (eg, autoclaving) can be related to the presence of PEG4000. Additionally or alternatively, the use of PEG 4000 as a surface modifier may be effective (e.g., with similar properties to allow for post-sterilization suspension and/or resuspension). Although it can be advantageous because it can replace the plastid, when the surface-modifying agent is replaced it cannot be tolerated (eg in humans) above a certain dose or amount (eg injectable). For example, other surface modifiers, such as Vitamin E TPGS, cannot be tolerated above a certain injectable dose in humans and therefore need to be replaced entirely or the dose/volume needs to be reduced. There is either

Micro- or nanosuspensions (without PEG 4000) may be sterilized by autoclaving and may be fully resuspendable (e.g. under conditions defined herein, especially for less than 40 seconds). may be resuspended by swirling), in which case PEG 4000 may not be required. However, in embodiments where resuspendability is not sufficient (e.g. requires more than 40 seconds), then the use of PEG 4000 or the like in such micro- or nano-suspensions is for example post-autoclave sterilization (i.e. It can help improve resuspension by making it easier (such as by reducing the time it takes to less than 40 seconds). The United States Pharmacopeia notes that the suspension should be redispersible, such as if the suspension settles on storage, and the goal is generally to minimize the time required to resuspend. It is to have a short suspension, so PEG 4000 (etc.) can help in this respect and in aspects of the present invention.

Hence, in view of the above, in a further embodiment of the invention:
- PEG 4000 or the like for use as a surface modifier in a pharmaceutical composition for administration by intramuscular or subcutaneous injection, said composition containing an active ingredient in the form of a suspension of micro- or nanoparticles PEG 4000, etc., comprising a drug component (e.g., bedaquiline), or a pharmaceutically acceptable salt thereof, characterized in that PEG 4000 serves, for example, to resuspend the composition after sterilization (e.g., autoclave sterilization) - Micro or PEG 4000 for use in resuspending a pharmaceutical composition comprising an active pharmaceutical ingredient (e.g., bedaquiline), or a pharmaceutically acceptable salt thereof, in the form of a suspension of nanoparticles, , such as PEG 4000, wherein the composition has undergone sterilization (eg, autoclave sterilization)—containing an active pharmaceutical ingredient (eg, bedaquiline), or a pharmaceutically acceptable salt thereof, in the form of a suspension of micro- or nanoparticles PEG 4000, etc., for use as a resuspension aid in pharmaceutical compositions, e.g., PEG 4000, e.g., wherein said composition has been subjected to sterilization (e.g., autoclave sterilization) - in the form of a suspension of micro- or nanoparticles. PEG 4000 and the like for use to enhance (or improve) the resuspendability of a pharmaceutical composition comprising an active pharmaceutical ingredient (e.g., bedaquiline), or a pharmaceutically acceptable salt thereof, such as PEG 4000 and the like are provided wherein the composition has undergone sterilization (eg, autoclave sterilization).

In all cases above, PEG 4000 and the like may be for such use in the pharmaceutical compositions described herein. Resuspendability can be compared to pharmaceutical compositions without PEG 4000 in certain circumstances.

In a further alternative embodiment,
- The use of PEG 4000 or the like as a surface modifier in pharmaceutical compositions containing an active pharmaceutical ingredient (e.g. bedaquiline), or a pharmaceutically acceptable salt thereof, in the form of a suspension of micro- or nanoparticles. PEG 4000 serves to resuspend said composition, for example after sterilization (for example autoclave sterilization) - an active pharmaceutical ingredient (for example bedaquiline) in the form of a suspension of micro- or nanoparticles, or pharmaceuticals thereof use of PEG 4000 etc. in the resuspension of a pharmaceutical composition comprising a pharmaceutically acceptable salt, e.g. where said composition has been subjected to sterilization (e.g. autoclave sterilization) - suspension of micro- or nanoparticles The use of PEG 4000 or the like as a resuspension aid in a pharmaceutical composition comprising an active pharmaceutical ingredient (e.g. bedaquiline), or a pharmaceutically acceptable salt thereof, in liquid form, e.g. is subjected to sterilization (e.g. autoclave sterilization) - resuspension of a pharmaceutical composition containing an active pharmaceutical ingredient (e.g. bedaquiline), or a pharmaceutically acceptable salt thereof, in the form of a suspension of micro- or nanoparticles Provided is the use of PEG 4000 or the like to enhance (or improve) turbidity, for example the composition has been subjected to sterilization (eg autoclave sterilization).

In all cases above, the use of PEG 4000 and the like can be in the pharmaceutical compositions described herein. Again, resuspendability can be compared to pharmaceutical compositions without PEG 4000 in certain circumstances.

The particles of the present invention can be obtained by mechanical means and by controlled precipitation from supersaturated solutions, or by the use of supercritical fluids, such as in the GAS technique (“gas antisolvent”), or any combination of such techniques. can be prepared by micronization/particle size reduction/nanopartization by In one embodiment, bedaquiline is dispersed in a liquid dispersion medium and mechanical means are applied in the presence of grinding media to reduce the particle size of bedaquiline to an average effective particle size of less than about 50 μm, particularly less than about 1,000 nm. A method is used that includes the step of allowing Particles can be reduced in size in the presence of surface modifiers.

A general procedure for preparing the particles of the invention is
(a) obtaining bedaquiline in micronized form;
(b) adding micronized bedaquiline to a liquid medium to form a premix/predispersion;
(c) subjecting the premix to mechanical means in the presence of grinding media to reduce the average effective particle size.

In certain embodiments,
(a) obtaining an active pharmaceutical ingredient (e.g., bedaquiline), or a pharmaceutically acceptable salt thereof, in micronized form;
(b) adding a micronized active ingredient (e.g., bedaquiline), or a pharmaceutically acceptable salt thereof, to a liquid medium to form a premix/pre-dispersion, wherein the liquid medium comprises: 2, 3 or 4, characterized in that it contains a surface modifier including PEG 4000 or the like;
(c) subjecting the premix to mechanical means in the presence of grinding media to reduce the average effective particle size;
(d) a step of sterilization (e.g. autoclave sterilization);
(e) resuspending (eg, if necessary).

In such cases, resuspension may be performed by swirling for less than 40 seconds. Certain embodiments provide for the use of PEG4000 in such methods.

Micronized forms of bedaquiline are prepared using techniques known in the art. Preferably, the average effective particle size of the bedaquiline active agent in the predispersion is less than about 100 μm as determined by sieve analysis. If the average effective particle size of micronized bedaquiline is greater than about 100 μm, the particles of bedaquiline compound are preferably reduced in size to less than 100 μm (eg, to a size or size range as described herein).

Micronized bedaquiline can then be added to a liquid medium in which it is essentially insoluble to form a predispersion. The concentration (weight/weight percentage) of bedaquiline in the liquid medium can vary widely and depends on the surface modifier selected and other factors. Suitable concentrations of bedaquiline in the composition are from about 0.1% to about 60%, or from about 1% to about 60%, or from about 10% to about 50%, or from about 10% to about 30%, such as about Varies by 10%, 20% or 30% (each % in this paragraph relates to w/v).

The premix can be used directly by subjecting it to mechanical means to reduce the average effective particle size in the dispersion to less than 2,000 nm. The premix is preferably used directly if a ball mill is used for grinding. Alternatively, the bedaquiline and, optionally, the surface modifier can be dispersed in the liquid medium using suitable agitation, for example a roller mill, until a uniform dispersion is achieved.

The mechanical means applied to reduce the effective average effective particle size of bedaquiline can conveniently take the form of a dispersion mill. Suitable dispersion mills include ball mills, attritor/grind mills, vibratory mills, planetary mills, media mills such as sand mills and bead mills. Media mills are preferred because of the relatively shorter milling times required to provide the desired reduction in particle size. The beads are preferably _ZrO2 beads. For example, for nanoparticles the ideal bead size is about 0.5 mm and for microparticles the ideal bead size is about 2 mm.

The grinding media for the particle size reduction step can be selected from hard media, preferably spherical or particulate in morphology (beads as small as 200 μm), with average dimensions of less than 3 mm, more preferably less than 1 mm. . Such media desirably can provide the particles of the invention in shorter processing times and cause less wear and tear on the milling equipment. Examples of grinding media are _ZrO2 , such as magnesia-stabilized or yttrium-stabilized 95% _ZrO2 , zirconium silicate, glass grinding media, polymeric beads, stainless steel, titania, alumina, and the like. Preferred grinding media have a density greater than 2.5 g/cm ³ , preferred grinding media include 95% ZrO ₂ stabilized with magnesia and polymeric beads.

Milling times can vary widely and depend primarily on the particular mechanical means and processing conditions chosen. For rolling mills, processing times of up to two days or more may be required.

The particles should be reduced in size at a temperature that does not significantly degrade the bedaquiline compound. Processing temperatures of less than 30°C to 40°C are generally preferred. If desired, the processing equipment may be cooled using conventional cooling equipment. The method is conveniently carried out under ambient temperature conditions and at process pressures that are safe and effective for the milling process.

Pharmaceutical compositions according to the invention preferably contain an aqueous carrier that is pharmaceutically acceptable. Said aqueous carriers comprise sterile water optionally mixed with other pharmaceutically acceptable ingredients. The latter includes optional ingredients for use in injectable formulations. Such ingredients are optional. These ingredients may be selected from one or more of suspending agents, buffers, pH adjusting agents, preservatives, tonicity agents, and similar ingredients. In one embodiment, said components are selected from one or more of suspending agents, buffering agents, pH adjusting agents, and optionally preservatives and tonicity agents. Certain ingredients may function as two or more of these agents simultaneously, eg, behave like preservatives and buffers, or like buffers and tonicity agents.

Suitable optional buffers and pH adjusters are sufficient to render the dispersion neutral to slightly basic (up to pH 8.5), preferably in the pH range of 7-7.5. should be used in moderate amounts. Particular buffers are salts of weak acids. Buffers and pH adjusters that can be added include tartaric acid, maleic acid, glycine, sodium lactate/lactic acid, ascorbic acid, sodium citrate/citric acid, sodium acetate/acetic acid, sodium bicarbonate/carbonic acid, sodium succinate/ Succinic acid, sodium benzoate/benzoic acid, sodium phosphate, tris(hydroxymethyl)aminomethane, sodium bicarbonate/sodium carbonate, ammonium hydroxide, benzenesulfonic acid, sodium benzoate/benzoic acid, diethanolamine, gluconodeltalactone , hydrochloric acid, hydrogen bromide, lysine, methanesulfonic acid, monoethanolamine, sodium hydroxide, tromethamine, gluconic acid, glyceric acid, glutaric acid, glutamic acid, ethylenediaminetetraacetic acid (EDTA), triethanolamine, mixtures thereof, etc. can be selected. In some embodiments, the compositions of the invention do not contain buffering agents. In some embodiments, especially when the pH is low, the compositions of the invention contain a buffering agent, such as a citrate-phosphate buffer.

Suitable optional preservatives include benzoic acid, benzyl alcohol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), chlorbutol, gallate, hydroxybenzoate, EDTA, phenol, chlorocresol, metacresol, Antimicrobial agents and antioxidants that can be selected from the group consisting of benzethonium chloride, myristyl-γ-picolinium chloride, phenylmercuric acetate and thimerosal. Radical scavengers include BHA, BHT, vitamin E and ascorbyl palmitate, and mixtures thereof. Oxygen scavengers include sodium ascorbate, sodium sulfite, L-cysteine, acetylcysteine, methionine, thioglycerol, acetone sodium bisulfite, isoacorbic acid, hydroxypropylcyclodextrin. Chelating agents include sodium citrate, sodium EDTA and malic acid. In some embodiments of the invention, the compositions of the invention do not contain preservatives.

An isotonizing agent or isotonifier may be present to ensure the isotonicity of the pharmaceutical composition of the present invention, examples of which include glucose, dextrose, sucrose, fructose, trehalose, lactose polyhydric sugar alcohols, preferably trihydric, tetrahydric or higher sugar alcohols, such as glycerin, erythritol, arabitol, xylitol, sorbitol and mannitol. Alternatively, sodium chloride, sodium sulfate, or other suitable inorganic salt may be used to make the solution isotonic. These tonicity agents can be used alone or in combination. The suspension conveniently contains 0-10% (w/v), especially 0-6%, of a tonicity agent. Non-ionic tonicity agents such as glucose are of interest because electrolytes can affect colloidal stability. In one embodiment of the invention, the composition of the invention contains a tonicity agent, which in a further embodiment is a non-ionic tonicity agent, eg a suitable sugar such as mannitol. The amount of tonicity agent is as previously described herein, but may also be added in a fixed ratio relative to bedaquiline, e.g. bedaquiline and tonicity agent (e.g. mannitol) w/ The w ratio can be from 1:1 to 10:1, such as from about 2:1 to 8:1, especially from about 3:1 to 6:1 (eg, about 4:1).

A desirable feature for the pharmaceutical compositions of the present invention relates to ease of administration. The viscosity of the pharmaceutical composition of the invention should be sufficiently low to allow administration by injection. In particular, they are easily picked up into a syringe (e.g. from a vial) and not too long to pass through a fine needle (e.g. a 20G 1 1/2, 21G 1 1/2, 22G 2 or 22G 1 1/4 needle). It should be designed so that it can be injected in time. In one embodiment, the viscosity of the composition of the present invention is less than about 75 mPa·s, or less than 60 mPa·s. Aqueous suspensions of such viscosities or less typically meet the above criteria.

Ideally, aqueous suspensions according to the invention contain as much bedaquiline (or a pharmaceutically acceptable salt thereof), especially 3-70% (w/v ), or 3-60% (w/v), 3-40% (w/v), 10-40% (w/v) of bedaquiline (or a pharmaceutically acceptable salt thereof) . In one embodiment, the aqueous suspension of the present invention comprises about 50%-70% (w/v) bedaquiline (or a pharmaceutically acceptable salt thereof), about 40%-60% (w/v) of bedaquiline (or a pharmaceutically acceptable salt thereof), or about 30% to 50% (w/v) of bedaquiline (or a pharmaceutically acceptable salt thereof).

In one embodiment, the aqueous suspension contains, by weight, based on the total volume of the composition:
(a) 10% to 70% (w/v), 20% to 60% (w/v), 20% to 50% (w/v), or 20% to 40% (w/v) of bedaquiline ( or a pharmaceutically acceptable salt thereof);
(b) 0.5% to 20% (w/v), or 2% to 15% or 20% (w/v), or 5% to 15% (w/v) of a humectant (herein Also called a surface modifier);
(c) one of 0% to 10% (w/v), 0% to 5% (w/v), 0% to 2% (w/v), or 0% to 1% (w/v) a buffer of the above;
(d) 0% to 20% (w/v), or 2% to 15% or 20% (w/v), or 5% to 15% (w/v) of a tonicity agent;
(e) 0% to 2% (w/v) of a preservative; and (f) a suitable amount of water for injection to make up 100% total.

In one embodiment, the aqueous suspension contains, by weight, based on the total volume of the composition:
(a) 3%-50% (w/v), 10%-40% (w/v), 10%-30% (w/v) of bedaquiline (or a pharmaceutically acceptable salt thereof);
(b) 0.5% to 10% (w/v), or 0.5% to 2% (w/v) of a humectant;
(c) one of 0% to 10% (w/v), 0% to 5% (w/v), 0% to 2% (w/v), or 0% to 1% (w/v) a buffer of the above;
(d) 0% to 10% (w/v), or 0% to 6% (w/v) of a tonicity agent;
(e) 0% to 2% (w/v) of a preservative; and (f) a suitable amount of water for injection to make up 100% total.

An amount of acid or base may optionally be added to the suspension to bring the pH to a value of about pH7. Suitable acids or bases are any of the physiologically acceptable ones, eg HCl, HBr, sulfuric acid, alkali metal hydroxides such as NaOH. In some embodiments, such acids or bases need not be added to the compositions of the invention.

Although administration of bedaquiline (or a pharmaceutically acceptable salt thereof) as in the present invention can be sufficient to treat pathogenic mycobacterial infections, often other anti-TB agents are co-administered. Dosing may be recommended.

In certain cases, treatment of pathogenic mycobacterial infections involves administration of bedaquiline (and/or its metabolites) compositions according to the invention, i. It may be limited to administration only as drug therapy. This option is e.g. against certain mycobacterial infections where low concentrations of the active ingredient may treat the bacteria (e.g. against latent/dormant TB or against Mycobacterium leprae). ) can be recommended.

In a further aspect, the present invention provides an effective amount of bedaquiline, or a pharmaceutically acceptable wherein the composition is administered or administered intermittently at time intervals ranging from 1 week to 1 year, or 1 week to 2 years. regarding use.

Thus, in a further aspect, the invention provides a method for the long-term treatment of patients infected with pathogenic mycobacterial infections (e.g. drug-resistant or latent/dormant mycobacteria), said method comprising:
(i) treatment of said patient with a combination of anti-TB agents; and subsequently (ii) an intermittent pharmaceutical composition according to the present invention comprising a therapeutically effective amount of bedaquiline or a pharmaceutically acceptable salt thereof. periodic administration (where the compositions are administered at time intervals of at least one week)
to provide a method comprising:

If the treatment is directed against Mycobacterium leprae, then again the treatment regimen may be either as a monotherapy or as an existing drug useful in the treatment of Mycobacterium leprae. (eg rifapentine). The compositions of the invention may be administered by injection once or up to three times, eg at monthly intervals. Benefits are associated with adherence, absence of resistance by avoiding dapsone, and absence of stigma by avoiding clofazimine.

The invention also relates to a pharmaceutical composition as hereinbefore described for use as a medicament in the treatment or prevention of pathogenic mycobacterial infections.

Additionally, the present invention relates to the use of a pharmaceutical composition as described herein for the preparation of a medicament for the prevention or treatment of pathogenic mycobacterial infections.

The invention further relates to a method of treating a subject infected with a pathogenic mycobacterial infection, said method comprising administering a therapeutically effective amount of a pharmaceutical composition as described herein.

As used herein, the word "substantially" does not exclude "completely", e.g., a composition "substantially free" of Y may be completely free of Y. If desired, the word "substantially" may be omitted from the definition of the invention. The term "about" in connection with numerical values is intended to have its ordinary meaning in connection with numerical values. Where appropriate, the word "about" may be replaced by a numerical value ±10%, or ±5%, or ±2%, or ±1%.

All documents cited herein are incorporated by reference in their entirety.

The following examples are intended to illustrate the invention and should not be construed as limiting the invention.

Process Example: Preparation of Micro- and Nanosuspensions The active ingredient bedaquiline may be used as is or its pharmaceutically acceptable salts, such as the fumarate (e.g. commercial product Sirturo®). form used in ). When referred to herein, bedaquiline is used in its non-salt form unless otherwise specified.

The prototype of the bedaquiline formulation is as follows:
Preparation of 200 mg/mL and 100 mg/mL nano- and micro-suspensions.

Raw materials used:
Zirconium beads 0.5 mm (to aid the process)
Sterile water for injection (Viaflo)
Bedaquiline (Unmilled/Unmilled)
Surface modifiers-excipients, such as PEG 4000 (etc.) and one or more other suitable surface modifiers (e.g. tocophenyl PEG 1000 succinate) Zirconium beads 2 mm (to aid the process)
Mannitol (parenteral) - Excipients Buffers (if necessary) eg citrate-phosphate buffer

Glass bottles and ZrO ₂ beads (either 0.5 mm or 2 mm depending on the desired nano- or micro-suspension) used as milling media were sterilized in an autoclave. Drug substance (amount depending on the formulation to be prepared; see e.g. Formulations/Suspensions below) and a solution of surface modifiers (e.g. PEG 4000 and tocopheryl PEG 1000 succinate) in water for injection (required (see formulations/suspensions below) were placed in glass vials. ZrO ₂ -beads with an average particle size of 500 μm or 2 mm (depending on whether a micro- or nano-suspension is needed/desired) were added. The jar was placed on a roller mill. The suspension was micronized/nanoparticulated at 100 rpm for periods of up to 72 hours. For example, micronization may be performed at 100 rpm for a period of 3 hours (or up to 3 hours) and nanoparticulation may be performed at 100 rpm for up to 46 hours (eg, about 40 hours). At the end of the milling process, the concentrated micro- or nanosuspension was removed with a syringe and filled into vials. The resulting formulations (based on nanosuspensions and microsuspensions) are described in the table below. Concentration determinations were made by HPLC/UV. If necessary, dilutions were made to give a final concentration of 200 mg/ml of the active ingredient bedaquiline. The resulting suspension was protected from light. Other concentrations were also produced and tested, such as 300 mg/ml and 100 mg/ml nano and micro formulations.

Such formulations have been (and will be) administered intramuscularly and subcutaneously to PK study animals to investigate possible long-acting effects (eg in the treatment of leprosy).

Physical stability of suspensions will be followed by measuring particle size after various storage conditions.

Certain embodiments of formulations are characterized by:
- microsuspension by using 2mm Zr beads - milling at 200mg/ml (otherwise the concentration may be too high, eg 300mg/ml)
- Longer milling, resulting in a nanosuspension - Suitable surface modifiers, e.g. selected based on physical stability, e.g. surface modifiers or wetting agents as described herein have.

Reference Examples of Bedaquiline Microsuspension 200 mg/ml microsuspension referred to herein as Reference Example A (without buffer) and Reference Examples B and C (with buffer)

Reference example A

Particle size distribution (PSD)

PSD measurements after 1 month show that the formulation remains relatively stable and the % volume density is also illustrated in Figure 1 (where "Concept 7" refers to Reference Example A).

Stability test using HPLC:
An HPLC test method was used to determine how stable the long-acting injectable formulation of Reference Example A was. The aim was to measure the amount of bedaquiline compared to two known degradants after a period of time at room temperature.

HPLC Procedure: Column - ProntoSIL 120-3-C18 SH, 100 mm length x 3.0 mm id, 3 μm particle size, or equivalent; column temperature 35° C.; autosampler temperature 5° C.; flow rate 0.5 mL/min; Wavelength 230 nm; Data acquisition time 50 min; Analysis run time 60 min; Injection volume 10 μl; Mobile phase A is 0.03 M hydrochloric acid in water; /10(v/v/v).

HPLC purity testing indicates that the formulation of Reference Example A is relatively stable over time (given that the relative amounts of degradants and bedaquiline remain stable).

Reference examples B and C

Particle size distribution (PSD)

The PSDs for these formulations under various conditions (such as after autoclave sterilization) show that the formulations remain relatively stable. This is illustrated in FIG. 2, where Concept 3 refers to Reference B and Concept 4 refers to Reference C.

Example 1 - Microsuspensions of the Invention The suspensions of the reference examples all contain vitamin E TPGS, which is administered parenterally, e.g. Not permissible for injection. Although Vitamin E TPGS does not have to be completely replaced (because, for example, 5 mg/ml is parenterally acceptable), the suspensions of the present invention contain Vitamin E TPGS (as a surface modifier). Advantageously reduce the amount. PEG 4000 (ie polyethylene glycol 4000) is used, which can be supplied by Clariant GmbH. PEG 4000 is a hydrophilic agent that can be used to increase the viscosity of suspension vehicles and can function as a suspending agent.

Example 1 Formulation

In this case, a buffer was added to avoid lowering the pH.

Particle size distribution (PSD)

The PSD of the microsuspension of Example 1 shows that the formulation remains relatively stable after autoclaving. This is shown in FIG.

A suitable cloud point for the formulation of Example 1 was calculated to be about 105-110°C.

Autoclave sterilization of the microsuspension of Example 1 was performed in a Systec autoclave (VX/VE series), where the parameters were:
Sterilization temperature: 121°C (above calculated cloud point)
Sterilization time: 15 minutes Unloading temperature: 80°C
is.

A typical autoclave sterilization cycle—a steam generator builds up the required steam pressure and steam volume into the sterilization chamber, and after reaching the sterilization temperature, it then remains constant for the duration of the sterilization period. After that period, it is cooled in an optional internal cooling device until the unloading temperature is reached.

Given that the autoclave sterilization temperature is above the measured cloud point, one would expect to see particle agglomeration, eg due to phase separation.

Further data on the microsuspension of Example 1 Particle size distribution (PSD) after subjecting the suspension to constant conditions

The above data for PSD also show that the microsuspension of Example 1 remains relatively stable after autoclave sterilization and after additional time (and at various temperatures), which is also outlined in FIG. is shown.

Resuspendability: After autoclaving, particles can be seen at the bottom of the container, which must therefore be shaken. Advantageously, when tested, the formulation of Example 1 was found to be readily resuspendable after shaking.

Further data on the microsuspension of Example 1 Particle size distribution (PSD) after subjecting the suspension to certain further conditions

It can be seen that the PSD is stable even after autoclave sterilization and even up to 3 months at 60° C., which is outlined in FIG.

The HPLC test method described above was used to determine how stable the long acting injectable formulation of Example 1 was. Again, the aim was to measure the amount of bedaquiline relative to known degradants/impurities after a period of time at room temperature, which gave the following results:

Conclusion An important conclusion is that the suspensions of Reference Example and of Example 1, even after autoclave sterilization, after storage for a period of time and at elevated temperature, as determined by purity measurements with PSD and HPLC test methods , is to be stable.

A further important conclusion was that the suspension of Example 1 was easily resuspendable after autoclave sterilization, even after storage for a period of time and at elevated temperatures.

Further Resuspendability Data

The resuspendability of the above compositions was objectively tested after autoclaving in the above examples by swirling the relevant compositions. The composition without PEG 4000 was difficult to resuspend (where it took more than 40 seconds to resuspend and required swirling and shaking), whereas the composition with PEG 4000 The articles were found to be relatively easy to resuspend where they required gentle swirling for less than 40 seconds.

Example 1A (Microsuspension)

Particle Size Distribution (PSD) and Resuspendability (Example 1A)

Example 1B (Microsuspension)

Particle Size Distribution (PSD) and Resuspendability (Example 1B)

Example 1C (Microsuspension)

Particle Size Distribution (PSD) and Resuspendability (Example 1C)

Example 1D (microsuspension)

Particle Size Distribution (PSD) and Resuspendability (Example 1D)

Example 1E (Microsuspension)

Particle Size Distribution (PSD) and Resuspendability (Example 1E)

Reference Example 1F (micro suspension)

Particle Size Distribution (PSD) and Resuspendability (Example 1F)

Example 2: Pharmacokinetic Studies Pharmacokinetic Studies in Mice, Rat and Beagle Dogs A number of studies in mice, rats and beagle dogs are described in WO2019/012100 and they generally demonstrated that sustained plasma concentrations of bedaquiline and/or its active metabolite M2 were seen over a period of time (such as 1 month, 3 months and 6 months) using, for example, the formulation of Reference Example A. are doing.

Pharmacokinetic Profile in Rat A formulation with a concentration of 200 mg/mL was used in this study and the microsuspension of Reference Example A was used, i.e., microparticles (of active bedaquiline) at a concentration of 200 mg/ml plus TPGS (4:1 bedaquiline:TPGS) and 50 mg/ml mannitol in WFI (water for injection), without buffer, were used. Bedaquiline is also referred to as TMC207.

These studies demonstrate that Reference Example A produced stable long-term plasma concentrations in male rats when administered subcutaneously (SC) and intramuscularly (IM).

Male rats The first experiment administered each relevant 200 mg/ml nanosuspension and microsuspension referred to above at a concentration of 40 mg/kg (0.2 mL/kg) subcutaneously (SC) and intramuscularly. It was performed in male rats that were administered by injection (IM). An interim analysis was performed at 3 months and results were followed up at 6 months. 12 rats were used in the study. Three rats were dosed intramuscularly (IM) with a 200 mg/ml microsuspension (see Reference Example A). Three rats were dosed subcutaneously (SC) with a 200 mg/ml microsuspension (see Reference Example A).

Phase 1 of results - up to 2200 hours Dynamics

The following parameters were calculated for TMC207 (see figure):

Where applicable, average values are given (with min → max in brackets)

Phase 2 of Results - Up to 4400 Hours In all cases plasma concentrations of BDQ or M2 are calculated as the mean of 3 rats in the relevant study.

Study in rats: for the formulation of Reference Example A, i.e. microsuspension, at 200 mg/ml concentration and dosed SC at 40 mg/kg (StDev = standard deviation) and dosed IM at 40 mg/kg

Plasma Concentration vs. Time-Profiles for Reference Example A and Example 1 In the figure below, the plasma concentration vs. time profiles for Reference Example A (labeled F4) and Example 1 (labeled F1) are 40 mg. /kg of SC injection were studied in rats. Concentrations of bedaquiline and its active metabolite M2 were measured.

Sustained parent compound plasma concentrations above the LLOQ (lower limit of quantification) were observed in all animals in all groups for the duration of the study. Two parent compound plasma concentration peaks (C _max ) were observed for both formulations F1 and F4 within the first 28 days after SC administration. General convergence of drug plasma concentrations to similar profiles and concentrations over time occurred for both formulations after 28 days.

FIG. 7 shows plasma concentration versus time profiles of subcutaneously administered bedaquiline LAI microsuspensions containing different surfactants (PEG4000 in combination with TPSG, and TPSG) in rats.

Regarding the plasma concentration-time profiles of M2 metabolites, again sustained plasma concentrations of M2 above the LLOQ were observed in all animals for both F1 and F4.

FIG. 8. Plasma concentrations of bedaquiline (BDQ) metabolites versus time after subcutaneous administration of BDQ (bedaquiline) LAI microsuspensions containing different surfactants (PEG4000 in combination with TPSG, and TPSG) in rats. Show your profile.

After intramuscular administration, again sustained plasma concentrations of the parent compound in excess of the LLOQ were observed in all animals for both F1 and F4 formulations for the duration of the study.

FIG. 9 shows plasma concentration versus time profiles of intramuscularly administered bedaquiline LAI microsuspensions containing different surfactants (PEG4000 combined with TPSG, and TPSG) in rats.

Similarly, sustained plasma concentrations were achieved for metabolites after intramuscular administration.

FIG. 10 shows plasma concentrations of bedaquiline (BDQ) metabolites versus plasma concentrations of bedaquiline (BDQ) metabolites after intramuscular administration of BDQ (bedaquiline) LAI microsuspensions containing different surfactants (PEG4000 in combination with TPSG, and TPSG) in rats. Shows the time profile.

Conclusion: Both formulations of Reference Example A (F4) and Example 1 (F1) are reasonably effective in achieving sustained release of both drug and active metabolite (M2) and both Therefore, it was suitable for such purposes.

Example 3
Evaluation of an injectable, long-acting bedaquiline formulation in a paucibacillary mouse model of latent tuberculosis infection (LTBI). Bactericidal activity of long-acting bedaquiline (B _LA ) formulations administered every 4 weeks for a total of 1, 2, or 3 doses was measured as a standard 25 mg/kg dose, or total drug dose administered as B _LA was to compare the activity of daily (5 days per week) oral dosing of B at lower doses consistent with . Table 1 shows the original research scheme. The _BLA used for this study is the microsuspension at the concentration described above in Reference Example A, ie 200 mg/ml). The primary outcome was a reduction in Mycobacterium tuberculosis lung CFU counts during treatment.

Regime justification o Untreated mice were used to determine the level and stability of paucibacillary infection.
o R ₁₀ (5/7) is an alternative regime for the treatment of LTBI in the United States and Canada and is administered for 4 months. It was used here as a control to qualify the model.
o P ₁₅ H ₅₀ (1/7) is an alternative regime for the treatment of LTBI in the United States, administered once weekly for 3 months (12 doses). It was found to be at least as effective as isoniazid for 9 months. It is the most intermittent of the currently recommended regimes and serves as a secondary control.
o B ₂₅ (5/7) is once-daily B at human-equivalent doses previously studied in the paucibacillus model. It provides a total dose of 500 mg/kg every 28 days.
o B ₈ (5/7) is reduced to provide the same total dose (480 mg/kg) as the _BLA formulation dose administered x3 doses every 28 days (i.e., 160 mg/kg) B once daily at dose.
o B _5.33 (5/7) was reduced to provide the same total dose (320 mg/kg) as the _BLA formulation dose administered x2 doses every 28 days (i.e., 160 mg/kg). B once daily at the recommended dose.
o B _2.67 (5/7) at doses that have been reduced to provide the same total dose (160 mg/kg) as the single administered _BLA formulation dose (i.e., 160 mg/kg) B once a day.
o B _LA-160 (1/28) x 3 is a B _LA formulation administered as 160 mg/kg for a total of 3 doses every 28 days. Therefore, the total B dose would match that of the B ₈ (5/7) group at each 28-day interval.
o B _LA-160 (1/28) x2 is a B _LA formulation administered as a total of 2 doses of 160 mg/kg every 28 days starting on day 0. Therefore, the total B dose administered at week 12 (320 mg/kg) would be the same as that of the B _5.33 (5/7) group.
o B _LA-160 (1/28) x 1 is a B _LA formulation administered as 160 mg/kg once on day 0. Therefore, the total B dose administered at week 12 (160 mg/kg) would be the same as that of the B _2.67 (5/7) group.

Final Results All CFU count data were finalized and presented in Table 2 below. Due to delays in finalizing the study site agreement and obtaining _BLA supplies, treatment was withdrawn from M.I. It does not begin until approximately 13 weeks after M. tuberculosis challenge infection, and the timeline in Table 2 has been adjusted accordingly. For comparisons between different treatment groups, statistical significance was assessed using one-way ANOVA adjusted with Bonferroni's multiple comparison test.

BCG immunization. 150 female BALB/c mice were infected with M. M. bovis rBCG30 was infected by aerosol. A culture suspension of OD ₆₀₀ of 1.03 was diluted 10-fold and then used for aerosol infection. The concentration of the bacterial suspension was 6.88 log ₁₀ CFU/mL, which resulted in a mean implantation of 3.05 (SD 0.10) log ₁₀ CFU/lung. Six weeks later, M. At the time of M. tuberculosis challenge, the average BCG load in mouse lungs was 4.95 (SD 0.11) log ₁₀ CFU. By day 0, the BCG load declined and stabilized at _3.27 (SD 0.45) logio CFU/lung, with similar lung loads observed in untreated mice at 4, 8, and 12 weeks. was done. Therefore, a low level, stable BCG infection was established in the lungs of these mice, as expected.

M. M. tuberculosis attack. Six weeks after BCG immunization, mice were challenged with M. M. tuberculosis H37Rv was infected by aerosol. A culture suspension of 0.850 OD ₆₀₀ was diluted approximately 100-fold and then used for aerosol infection. The concentration of the bacterial suspension was 4.73 log ₁₀ CFU/mL, which resulted in a mean implantation of 2.11 (SD 0.09) log ₁₀ CFU/lung. This implantation was approximately 1 log ₁₀ CFU higher than intended. By day 0, M. M. tuberculosis burden stabilized at approximately 4.8 log ₁₀ CFU/lung, and a similar lung burden was observed in untreated mice at 4, 8, and 12 weeks. Therefore, despite higher implantation, stable M. A M. tuberculosis infection was established in the lungs of these mice, and accordingly the stabilized lung CFU burden was approximately 1 log ₁₀ CFU higher than observed in previous experiments (1-3). it was high.

Evaluation of bactericidal activity (Table 2). M. pneumoniae in the lungs of untreated mice. Compared to M. tuberculosis CFU counts, the R ₁₀ (5/7) control regimen reduced mean CFU counts to approximately 1, 2, and 3 log ₁₀ after 4, 8, and 12 weeks of treatment, respectively. Only CFU/lung was reduced. The P ₁₅ H ₅₀ (1/7) control regime produced approximately 2, 3, and 4.5 log ₁₀ CFU reductions after 4, 8, and 12 weeks of treatment, respectively. The relative magnitude of reduction in lung CFU counts for both control regimes is as expected based on previous studies (1, 2). B ₂₅ (5/7) produced approximately 1.7, 4.0, and 4.9 log ₁₀ CFU/lung reductions after 4, 8, and 12 weeks of treatment, results also consistent with previous studies (1 2) as expected. Therefore, higher implantation and day 0 CFU counts did not affect the relative activity of the drug against this stabilized bacterial population in the mouse lung.

Increasing activity with increasing dose was observed at weeks 4, 8, and 12 for all B study regimes. For mice receiving 1 or 2 doses of B _LA-160 (1/28), a reduction in lung CFU counts compared to untreated mice was observed on the once-daily oral regimen for 4 or 8 weeks, respectively. , equivalent to a reduction in mice receiving the same total dose administered as B ₈ (5/7) (p>0.05 at both time points). A single dose of B _LA-160 , delivering 160 mg/kg on day 0, produced a reduction in approximately 1.3 log ₁₀ CFU/lung, and B ₈ (5/7) over 4 weeks was approximately 1.3 log 10 CFU/lung. Resulting in a reduction of 5 log ₁₀ CFU/lung. After two doses of B _LA-160 (1/28) or 8 weeks of B ₈ (5/7), intrapulmonary CFU counts increased by an additional 1 log ₁₀ in mice receiving either of these regimes. Decreased. After 12 weeks of treatment, intrapulmonary CFU counts were significantly higher than those in mice that received a single dose of B _LA-160 by once daily dosing of B _2.67 (5/7) (p=0.0002). Lower than in mice receiving the same total dose of bedaquiline (160 mg/kg), the former regime resulted in a reduction of approximately 3 log ₁₀ CFU/lung, compared to intrapulmonary counts in untreated control mice, the latter produced a reduction of approximately 1.7 log ₁₀ CFU/lung. In mice receiving a total bedaquiline dose of 320 mg/kg either by two doses of B _LA-160 or by B _5.33 (5/7) once daily dosing, the reduction in lung CFU counts was , with approximately 3 log ₁₀ CFU/lung (p>0.05). For mice receiving a total bedaquiline dose of 480 mg/kg with 3 doses of B _LA-160 (1/28), lung CFU counts were comparable with once daily dosing of B ₈ (5/7). Although higher than in mice receiving the total dose, the difference was not statistically significant.

After 12 weeks of treatment, nearly all test regimes had bactericidal activity equal to the R ₁₀ (5/7) control regime, and only the B _2.67 (5/7) regime had significantly lower bactericidal activity than this control. (p<0.0001). Test regime B ₈ (5/7) demonstrated bactericidal activity equivalent to both P ₁₅ H ₅₀ (1/7) and B ₂₅ (5/7) control regimes, while all other test regimes At 12 weeks, it was significantly less bactericidal than either of these control regimes. However, the CFU data recorded at week 12 may not reflect the overall efficacy of the long-acting bedaquiline regime. In mice receiving a single dose of BLA _-160 on day 0, sterilization was still observed 12 weeks after dosing. Therefore, it is conceivable that the bacterial burden in the lungs of mice receiving 2 and 3 doses of BLA _-160 would still be reduced further for at least 12 weeks after administration of the last dose. A single dose of BLA _-160 also appeared to exert greater bactericidal activity at weeks 1-4 and 9-12 compared to weeks 5-8 after dosing, and had a longer duration of action. It is interesting to note the possibility of biphasic B release kinetics from type vehicles.

CONCLUSIONS o Despite higher than expected bacterial implantation, stable M . M. tuberculosis infection was established in BALB/c mice, which were suitable for evaluation of LTBI treatment regimens.
o After 12 weeks of treatment, once-monthly dosing of BLA _-160 was superior to once-daily dosing for total bedaquiline doses of 160 or 320 and 480 mg/kg, respectively, or Equivalent bactericidal activity was demonstrated.
o Bactericidal activity observed from a single dose of _BLA-160 was evident for at least 12 weeks after dosing, presumably because CFU counts continued to decline in the lungs of mice receiving 2 and 3 doses. be. Taken together with the higher than expected baseline bacterial load in this experiment, these findings suggest that healing after 2 or 3 injections may be possible. Therefore, it will be critical to evaluate the bactericidal action of these _BLA regimes over a longer period of time to truly understand their potential for use in treating LTBI.

References 1) Zhang, T.; , Li, S.; , Williams, K.; , Andries, K.; , Nuermberger, E.; 2011. Short-course chemotherapy with TMC207 and rifapentine in a murine model of latent tuberculosis infection. Am. J Respir. Crit. Care Med. 184:732-737.
2) Lanoix, J.; P. , Betoudji, F.; , Nuermberger, E.; 2014. Novel regimes identified in mice for treatment of latent tuberculosis infection in contacts of multidrug-resistant tuberculosis cases. Antimicrob. Agents Chemother. 58:2316-2321.
3) Zhang, T.; , M. Zhang, I. M. Rosenthal, J.; H. Grosset, andE. L. Nuermberger. 2009. Short-course therapy with daily rifapentine in a murine model of latent tuberculosis infection. Am. J Respir. Crit Care Med. 180:1151-1157.

Claims (26)

A pharmaceutical composition for administration by intramuscular or subcutaneous injection comprising a therapeutically effective amount of bedaquiline, or a pharmaceutically acceptable salt thereof, in the form of a suspension of micro- or nanoparticles, said micro- or nanoparticles A suspension of
(a) bedaquiline, or a pharmaceutically acceptable salt thereof, in micro- or nanoparticulate form, and a surface modifier;
(b) by intramuscular or subcutaneous injection of a therapeutically effective amount of bedaquiline, or a pharmaceutically acceptable salt thereof, in the form of a micro- or nanoparticle suspension comprising a pharmaceutically acceptable aqueous carrier; A pharmaceutical composition for administration comprising:
The composition, wherein the surface modifier contains PEG4000 or the like. 2. The composition of claim 1, wherein the surface modifier comprises at least 75% by weight of PEG 4000 or the like, the balance being one or more other suitable surface modifiers. The one or more other suitable surface modifiers are selected from the group of poloxamers, α-tocopheryl polyethylene glycol succinates, polyoxyethylene sorbitan fatty acid esters, and salts of negatively charged phospholipids, according to claim 1. 2. The composition according to 2. 4. A composition according to claim 3, wherein said other surface modifier represents one surface modifier which is α-tocopheryl polyethylene glycol succinate (TPGS). A composition according to any one of claims 1 to 4, wherein bedaquiline is in its non-salt form, ie in its free form, or in the form of its fumarate salt. The composition according to any one of claims 1 to 5, wherein bedaquiline, or a pharmaceutically acceptable salt thereof, micro- or nanoparticles has an average effective particle size of less than about 50 µm, in particular less than about 200 nm. By weight based on the total volume of the composition,
(a) 10% to 70% (w/v), 20% to 60% (w/v), 20% to 50% (w/v), or 20% to 40% (w/v) of bedaquiline ( or a pharmaceutically acceptable salt thereof; but where said w/v is calculated based on its non-salt form);
(b) 0.5% to 20% (w/v), 2% to 15% or 20% (w/v), or 5% to 15% (w/v) of a wetting agent (or surface modifier) , that is, including PEG4000, etc.);
(c) one of 0% to 10% (w/v), 0% to 5% (w/v), 0% to 2% (w/v), or 0% to 1% (w/v) a buffer of the above;
(d) 0% to 20% (w/v), 2% to 15% or 20% (w/v), or 5% to 15% (w/v) of a tonicity agent;
3. The composition of claim 1 or 2, comprising (e) 0% to 2% (w/v) of a preservative; and (f) an appropriate amount of water for injection to make 100% total. Use of a pharmaceutical composition according to any one of claims 1-7 for the manufacture of a medicament for the treatment of pathogenic mycobacterial infections. 8. The medicament is for long-term treatment of Mycobacterium tuberculosis (such as drug-resistant or latent/dormant forms) or Mycobacterium leprae. Use as described. 9. Use according to claim 8, wherein said medicament is for administration by intramuscular or subcutaneous injection; said composition is administered intermittently at time intervals of one week to two years. Use according to claim 8, wherein the pharmaceutical composition is administered at intervals of at least one month to one year. Said pharmaceutical composition is in the range of 1 week to 1 month, or in the range of 1 month to 3 months, or in the range of 3 months to 6 months, or in the range of 6 months to 12 months, or in the range of 12 months to 24 months. 9. Use according to claim 8, administered at a time interval of . 9. Use according to claim 8, wherein the pharmaceutical composition is administered once every two weeks, or once every month, or once every three months. (a) obtaining bedaquiline, or a pharmaceutically acceptable salt thereof, in micronized form;
(b) adding said micronized bedaquiline, or a pharmaceutically acceptable salt thereof, to a liquid medium to form a premix/predispersion;
(c) subjecting the premix to mechanical means in the presence of grinding media to reduce the average effective particle size. way for. 15. A method according to claim 14, followed by sterilization, for example autoclave sterilization. 16. The method of claim 15, followed by resuspension. 17. The method of claim 16, wherein said resuspending comprises swirling said composition after sterilization for less than 40 seconds. PEG 4000 or the like for use as a surface modifier in a pharmaceutical composition for administration by intramuscular or subcutaneous injection, said composition comprising an active agent in the form of a suspension of micro- or nanoparticles. PEG 4000, etc., comprising a component (eg, bedaquiline), or a pharmaceutically acceptable salt thereof, characterized in that PEG 4000 helps resuspend the composition after sterilization (eg, autoclave sterilization). A pharmaceutical composition comprising an active pharmaceutical ingredient (e.g. bedaquiline), or a pharmaceutically acceptable salt thereof, in the form of a suspension of micro- or nanoparticles, said composition being sterilized (e.g. autoclave sterilized) PEG 4000, etc., for use in resuspending receiving compositions. PEG4000, etc., for use according to claim 18 or claim 19, wherein the pharmaceutical composition is as defined in any one of claims 1-7. Use of PEG 4000 or the like as a surface modifier in a pharmaceutical composition comprising an active pharmaceutical ingredient (e.g. bedaquiline), or a pharmaceutically acceptable salt thereof, in the form of a suspension of micro- or nanoparticles, , wherein the PEG 4000 helps resuspend the composition after sterilization (eg, autoclaving). A pharmaceutical composition comprising an active pharmaceutical ingredient (e.g. bedaquiline), or a pharmaceutically acceptable salt thereof, in the form of a suspension of micro- or nanoparticles, said composition being subjected to sterilization (e.g. autoclave sterilization) use of PEG 4000 or the like in the process of resuspending the composition. Use according to claim 21 or claim 22, wherein the pharmaceutical composition is as defined in any one of claims 1-7. (a) obtaining an active pharmaceutical ingredient (e.g., bedaquiline), or a pharmaceutically acceptable salt thereof, in micronized form;
(b) adding said micronized active ingredient (e.g. bedaquiline), or a pharmaceutically acceptable salt thereof, to a liquid medium to form a premix/pre-dispersion, said liquid medium comprising the 1, 2, 3 or 4, characterized by containing a surface modifier including PEG4000;
(c) subjecting the premix to mechanical means in the presence of grinding media to reduce the average effective particle size;
(d) sterilization (e.g. autoclave sterilization);
(e) resuspending (if necessary). 25. The method of claim 24, wherein said resuspending is performed by swirling for less than 40 seconds. Use of PEG4000 in the method of claim 24 or claim 25.